Cellular and Molecular Life Sciences

, Volume 74, Issue 17, pp 3205–3224 | Cite as

Functions of intrinsic disorder in transmembrane proteins

  • Magnus KjaergaardEmail author
  • Birthe B. Kragelund
Multi-author Review


Intrinsic disorder is common in integral membrane proteins, particularly in the intracellular domains. Despite this observation, these domains are not always recognized as being disordered. In this review, we will discuss the biological functions of intrinsically disordered regions of membrane proteins, and address why the flexibility afforded by disorder is mechanistically important. Intrinsically disordered regions are present in many common classes of membrane proteins including ion channels and transporters; G-protein coupled receptors (GPCRs), receptor tyrosine kinases and cytokine receptors. The functions of the disordered regions are many and varied. We will discuss selected examples including: (1) Organization of receptors, kinases, phosphatases and second messenger sources into signaling complexes. (2) Modulation of the membrane-embedded domain function by ball-and-chain like mechanisms. (3) Trafficking of membrane proteins. (4) Transient membrane associations. (5) Post-translational modifications most notably phosphorylation and (6) disorder-linked isoform dependent function. We finish the review by discussing the future challenges facing the membrane protein community regarding protein disorder.


Intrinsically disordered protein Membrane protein Receptor associated signalling complex Ball-and-chain inhibition Lipid interaction domain 



M.K is supported by Grants from the Villum Foundation and a COFUND fellowship from AIAS. B.B.K. is supported by the Danish Research Councils (DFF—4181-00344) and the Novo Nordisk Foundation SYNERGY program. Michael V. Clausen, Katie Kemplen, and Stine F. Petersen are thanked from critical comments to the manuscript.


  1. 1.
    Fernandez-leiro R, Scheres SHW (2016) Unravelling biological macromolecules with cryo-electron microscopy. Nature 537:339–346PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Pedersen BP, Nissen P (2015) Membrane proteins—do we catch up with the breathless pace of soluble protein structural biology? Biochim Biophys Acta Gen Subj 1850:447–448CrossRefGoogle Scholar
  3. 3.
    Dunker AK et al (2013) What’s in a name? Why these proteins are intrinsically disordered. Intrinsically Disord Proteins 1:1–5CrossRefGoogle Scholar
  4. 4.
    Uversky VN, Oldfield CJ, Dunker AK (2008) Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys 37:215–246PubMedCrossRefGoogle Scholar
  5. 5.
    Jensen MR, Ruigrok RWH, Blackledge M (2013) Describing intrinsically disordered proteins at atomic resolution by NMR. Curr Opin Struct Biol 23:426–435PubMedCrossRefGoogle Scholar
  6. 6.
    Jensen MR, Zweckstetter M, Huang J-R, Blackledge M (2014) Exploring free-energy landscapes of intrinsically disordered proteins at atomic resolution using NMR spectroscopy. Chem Rev 114:6632–6660PubMedCrossRefGoogle Scholar
  7. 7.
    Babu MM (2016) The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease. Biochem Soc Trans 44:1185–1200PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Tovo-Rodrigues L et al (2016) The role of protein intrinsic disorder in major psychiatric disorders. Am J Med Genet B Neuropsychiatr Genet 171:848–860PubMedCrossRefGoogle Scholar
  9. 9.
    Aguzzi A, Altmeyer M (2016) Phase separation: linking cellular compartmentalization to disease. Trends Cell Biol 26:547–558PubMedCrossRefGoogle Scholar
  10. 10.
    Ambadipudi S, Zweckstetter M (2015) Targeting intrinsically disordered proteins in rational drug discovery. Expert Opin Drug Discov 441:1–13Google Scholar
  11. 11.
    Teilum K, Olsen JG, Kragelund BB (2009) Functional aspects of protein flexibility. Cell Mol Life Sci 66:2231–2247PubMedCrossRefGoogle Scholar
  12. 12.
    Dyson HJ, Wright PE (2005) Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6:197–208PubMedCrossRefGoogle Scholar
  13. 13.
    Uversky VN, Gillespie JR, Fink AL (2000) Why are ‘natively unfolded’ proteins unstructured under physiologic conditions? Proteins 41:415–427PubMedCrossRefGoogle Scholar
  14. 14.
    He B et al (2009) Predicting intrinsic disorder in proteins: an overview. Cell Res 19:929–949PubMedCrossRefGoogle Scholar
  15. 15.
    Dosztányi Z, Csizmok V, Tompa P, Simon I (2005) IUPred: Web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics 21:3433–3434PubMedCrossRefGoogle Scholar
  16. 16.
    Jones DT, Cozzetto D (2015) DISOPRED3: precise disordered region predictions with annotated protein-binding activity. Bioinformatics 31:857–863PubMedCrossRefGoogle Scholar
  17. 17.
    Xue B, Dunbrack RL, Williams RW, Dunker AK, Uversky VN (2010) PONDR-FIT: a meta-predictor of intrinsically disordered amino acids. Biochim Biophys Acta 1804:996–1010PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Lyons JA, Shahsavar A, Paulsen PA, Pedersen BP, Nissen P (2016) Expression strategies for structural studies of eukaryotic membrane proteins. Curr Opin Struct Biol 38:137–144PubMedCrossRefGoogle Scholar
  19. 19.
    Bugge K, Steinocher H, Brooks AJ, Lindor K, Kragelund BB (2015) Exploiting hydrophobicity for efficient production of transmembrane helices for structure determination by NMR spectroscopy. Anal Chem 87:9126–9131PubMedCrossRefGoogle Scholar
  20. 20.
    Huber AH, Stewart DB, Laurents DV, Nelson WJ, Weis WI (2001) The cadherin cytoplasmic domain is unstructured in the absence of beta-catenin. A possible mechanism for regulating cadherin turnover. J Biol Chem 276:12301–12309PubMedCrossRefGoogle Scholar
  21. 21.
    Nørholm A-B et al (2011) The intracellular distal tail of the Na+/H+ exchanger NHE1 is intrinsically disordered: implications for NHE1 trafficking. Biochemistry 50:3469–3480PubMedCrossRefGoogle Scholar
  22. 22.
    Haxholm GW et al (2015) Intrinsically disordered cytoplasmic domains of two cytokine receptors mediate conserved interactions with membranes. Biochem J 468:495–506PubMedCrossRefGoogle Scholar
  23. 23.
    De Biasio A et al (2008) Prevalence of intrinsic disorder in the intracellular region of human single-pass type i proteins: the case of the notch ligand delta-4. J Proteome Res 7:2496–2506PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Ichiyama S et al (2006) The structure of the third intracellular loop of the muscarinic acetylcholine receptor M2 subtype. FEBS Lett 580:23–26PubMedCrossRefGoogle Scholar
  25. 25.
    Kalthoff C (2003) A novel strategy for the purification of recombinantly expressed unstructured protein domains. J Chromatogr B Anal Technol Biomed Life Sci 786:247–254CrossRefGoogle Scholar
  26. 26.
    Livernois AM, Hnatchuk DJ, Findlater EE, Graether SP (2009) Obtaining highly purified intrinsically disordered protein by boiling lysis and single step ion exchange. Anal Biochem 392:70–76PubMedCrossRefGoogle Scholar
  27. 27.
    Campos F, Guillén G, Reyes JL, Covarrubias AA (2011) A general method of protein purification for recombinant unstructured non-acidic proteins. Protein Expr Purif 80:47–51PubMedCrossRefGoogle Scholar
  28. 28.
    Brown CJ et al (2002) Evolutionary rate heterogeneity in proteins with long disordered regions. J Mol Evol 55:104–110PubMedCrossRefGoogle Scholar
  29. 29.
    Brown CJ, Johnson AK, Dunker AK, Daughdrill GW (2011) Evolution and disorder. Curr Opin Struct Biol 21:441–446PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Buljan M et al (2013) Alternative splicing of intrinsically disordered regions and rewiring of protein interactions. Curr Opin Struct Biol 23:443–450PubMedCrossRefGoogle Scholar
  31. 31.
    Iakoucheva LM et al (2004) The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res 32:1037–1049PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Tyanova S, Cox J, Olsen J, Mann M, Frishman D (2013) Phosphorylation variation during the cell cycle scales with structural propensities of proteins. PLoS Comput Biol 9(1):e1002842PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Habchi J, Tompa P, Longhi S, Uversky VN (2014) Introducing protein intrinsic disorder. Chem Rev 114:6561–6588PubMedCrossRefGoogle Scholar
  34. 34.
    Bah A et al (2015) Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch. Nature 519:106–109PubMedCrossRefGoogle Scholar
  35. 35.
    Grosely R et al (2013) Effects of phosphorylation on the structure and backbone dynamics of the intrinsically disordered connexin43 C-terminal domain. J Biol Chem 288:24857–24870PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Rosenlöw J, Isaksson L, Mayzel M, Lengqvist J, Orekhov VY (2014) Tyrosine phosphorylation within the intrinsically disordered cytosolic domains of the B-cell receptor: an NMR-based structural analysis. PLoS One 9:e96199PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Malaney P, Pathal RR, Xue B, Uversky VN, Dave V (2013) Intrinsic disorder in PTEN and its interactome confers structural plasticity and functional versatility. Sci Rep 3:2035PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Warne T et al (2011) The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor. Nature 469:241–244PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Rosenbaum DM et al (2007) GPCR engineering yields high resolution insight into β2-adrenergic receptor function. Science 318:1266–1273PubMedCrossRefGoogle Scholar
  40. 40.
    Moeller A, Lee SC, Carragher B, Zhang Q (2015) Distinct conformational spectrum of homologous multidrug ABC transporters. Struct Des 23:450–460CrossRefGoogle Scholar
  41. 41.
    Bernadó P, Svergun DI (2012) Structural analysis of intrinsically disordered proteins by small-angle X-ray scattering. Mol Biosyst 8:151–167PubMedCrossRefGoogle Scholar
  42. 42.
    Kjaergaard M, Poulsen FM (2012) Disordered proteins studied by chemical shifts. Prog Nucl Magn Reson Spectrosc 60:42–51PubMedCrossRefGoogle Scholar
  43. 43.
    Bugge K et al (2016) A combined computational and structural model of the full-length human prolactin receptor. Nat Commun 7:11578PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Van Den Bedem H, Fraser JS (2015) Integrative, dynamic structural biology at atomic resolution—it’s about time. Nat Methods 12:307–318PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Kjaergaard M (2015) Can proteins be intrinsically disordered inside a membrane? Intrinsically Disord Proteins 3:1–7CrossRefGoogle Scholar
  46. 46.
    Raucci R, Costantini S, Castello G, Colonna G (2014) An overview of the sequence features of N- and C-terminal segments of the human chemokine receptors. Cytokine 70:141–150PubMedCrossRefGoogle Scholar
  47. 47.
    Tovo-Rodrigues L, Roux A, Hutz MH, Rohde LA, Woods AS (2014) Functional characterization of G-protein-coupled receptors: a bioinformatics approach. Neuroscience 277:764–779PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Minezaki Y, Homma K, Nishikawa K (2007) Intrinsically disordered regions of human plasma membrane proteins preferentially occur in the cytoplasmic segment. J Mol Biol 368:902–913PubMedCrossRefGoogle Scholar
  49. 49.
    Bürgi J, Xue B, Uversky VN, Van Der Goot FG (2016) Intrinsic disorder in transmembrane proteins: roles in signaling and topology prediction. PLoS One 11:1–21CrossRefGoogle Scholar
  50. 50.
    Kurup K, Dunker AK, Krishnaswamy S (2013) Functional fragments of disorder in outer membrane β barrel proteins. Intrinsically Disord Proteins 1:e24848PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Pryor EE, Wiener MC (2014) A critical evaluation of in silico methods for detection of membrane protein intrinsic disorder. Biophys J 106:1638–1649PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Tusnády GE, Dobson L, Tompa P (2015) Disordered regions in transmembrane proteins. Biochim Biophys Acta Biomembr 1848:2839–2848CrossRefGoogle Scholar
  53. 53.
    Xie H et al (2007) Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions. J Proteome Res 6:1882–1898PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Sigalov AB, Uversky VN, Sigalov AB, Uversky VN (2011) Differential occurrence of protein intrinsic disorder in the cytoplasmic signaling domains of cell receptors differential occurrence of protein intrinsic disorder in the cytoplasmic signaling domains of cell receptors. Self Nonself 2:55–72PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Wong W, Scott JD (2004) AKAP signalling complexes: focal points in space and time. Nat Rev Mol Cell Biol 5:959–970PubMedCrossRefGoogle Scholar
  56. 56.
    Calebiro D, Maiellaro I (2014) cAMP signaling microdomains and their observation by optical methods. Front Cell Neurosci 8:350PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Llinás R, Sugimori M, Silver RB (1992) Microdomains of high calcium concentration in a presynaptic terminal. Science 256:677–679PubMedCrossRefGoogle Scholar
  58. 58.
    Choi UB, Xiao S, Wollmuth LP, Bowen ME (2011) Effect of Src kinase phosphorylation on disordered C-terminal domain of N-methyl-d-aspartic acid (NMDA) receptor subunit GluN2B protein. J Biol Chem 286:29904–29912PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Choi UB et al (2013) Modulating the intrinsic disorder in the cytoplasmic domain alters the biological activity of the N-methyl-d-aspartate-sensitive glutamate receptor. J Biol Chem 288:22506–22515PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Ryan TJ, Emes RD, Grant SG, Komiyama NH (2008) Evolution of NMDA receptor cytoplasmic interaction domains: implications for organisation of synaptic signalling complexes. BMC Neurosci 9:6PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11:682–696PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Hardingham GE, Fukunaga Y, Bading H (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 5(5):405–414PubMedGoogle Scholar
  63. 63.
    Stratton M et al (2014) Activation-triggered subunit exchange between CaMKII holoenzymes facilitates the spread of kinase activity. Elife 3:e01610PubMedCentralGoogle Scholar
  64. 64.
    Lisman J, Yasuda R, Raghavachari S (2012) Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci 13:169–182PubMedPubMedCentralGoogle Scholar
  65. 65.
    Strack S, Colbran RJ (1998) Autophosphorylation-dependent targeting of calcium/calmodulin-dependent protein kinase II by the NR2B subunit of the N-methyl-d-aspartate receptor. J Biol Chem 273:20689–20692PubMedCrossRefGoogle Scholar
  66. 66.
    Bayer KU, De Koninck P, Leonard AS, Hell JW, Schulman H (2001) Interaction with the NMDA receptor locks CaMKII in an active conformation. Nature 411:801–805PubMedCrossRefGoogle Scholar
  67. 67.
    Leonard AS, Lim IA, Hemsworth DE, Horne MC, Hell JW (1999) Calcium/calmodulin-dependent protein kinase II is associated with the N-methyl-d-aspartate receptor. Proc Natl Acad Sci USA 96:3239–3244PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Chao LH et al (2011) A mechanism for tunable autoinhibition in the structure of a human Ca2+/calmodulin-dependent kinase II holoenzyme. Cell 146:732–745PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Fischer E (1894) Effects of configuration on enzyme activity. Ber Dtsch Chem Ges 27:2985–2993CrossRefGoogle Scholar
  70. 70.
    Ehlers MD, Zhang S, Bernhardt JP, Huganir RL (1996) Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 Subunit. Cell 84:745–755PubMedCrossRefGoogle Scholar
  71. 71.
    Wyszynski M et al (1997) Competitive binding of alpha-actinin and calmodulin to the NMDA receptor. Nature 385:439–442PubMedCrossRefGoogle Scholar
  72. 72.
    Lin JW et al (1998) Yotiao, a novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1. J Neurosci 18:2017–2027PubMedGoogle Scholar
  73. 73.
    Lee FJS et al (2002) Dual regulation of NMDA receptor functions by direct protein–protein interactions with the dopamine D1 receptor. Cell 111:219–230PubMedCrossRefGoogle Scholar
  74. 74.
    Esseltine JL, Scott JD (2013) AKAP signaling complexes: pointing towards the next generation of therapeutic targets? Trends Pharmacol Sci 34:648–655PubMedCrossRefGoogle Scholar
  75. 75.
    Piggott LA, Bauman AL, Scott JD, Dessauer CW (2008) The A-kinase anchoring protein Yotiao binds and regulates adenylyl cyclase in brain. Proc Natl Acad Sci 105:13835–13840PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Fraser IDC et al (2000) β2-Adrenergic receptor assembly of an A kinase-anchoring protein—β complex facilitates receptor phosphorylation and signaling. Curr Biol 10:409–412PubMedCrossRefGoogle Scholar
  77. 77.
    Smith FD et al (2013) Intrinsic disorder within an AKAP-protein kinase A complex guides local substrate phosphorylation. Elife 2013:1–19Google Scholar
  78. 78.
    Bauman AL et al (2006) Dynamic regulation of cAMP synthesis through anchored PKA-adenylyl cyclase V/VI complexes. Mol Cell 23:925–931PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Lefkowitz RJ (1998) G protein-coupled receptors. J Biol Chem 273:18677–18681PubMedCrossRefGoogle Scholar
  80. 80.
    Crump FT, Dillman KS, Craig AM (2001) cAMP-dependent protein kinase mediates activity-regulated synaptic targeting of NMDA receptors. J Neurosci 21:5079–5088PubMedGoogle Scholar
  81. 81.
    Skeberdis VA et al (2006) Protein kinase A regulates calcium permeability of NMDA receptors. Nat Neurosci 9:501–510PubMedCrossRefGoogle Scholar
  82. 82.
    Aman TK, Maki BA, Ruffino TJ, Kasperek EM, Popescu GK (2014) Separate intramolecular targets for protein kinase A control N-methyl-d-aspartate receptor gating and Ca2+ permeability. J Biol Chem 289:18805–18817PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Coghlan VM et al (1995) Association of protein kinase A and protein phosphatase 2B with a common anchoring protein. Science 267:108–111PubMedCrossRefGoogle Scholar
  84. 84.
    Perham RN (1975) Self-assembly of biological macromolecules. Philos Trans R Soc Lond B Biol Sci 272:123–136PubMedCrossRefGoogle Scholar
  85. 85.
    Laba JK et al (2015) Active nuclear import of membrane proteins revisited. Cells 4:653–673PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Davey NE et al (2012) Attributes of short linear motifs. Mol Biosyst 8:268–281PubMedCrossRefGoogle Scholar
  87. 87.
    Van Roey K et al (2014) Short linear motifs: ubiquitous and functionally diverse protein interaction modules directing cell regulation. Chem Rev 114:6733–6778PubMedCrossRefGoogle Scholar
  88. 88.
    Kalderon D, Roberts BL, Richardson WD, Smith AE, Hill M (1984) A short amino acid sequence able to specify nuclear location. Cell 39:499–509PubMedCrossRefGoogle Scholar
  89. 89.
    Chica C, Diella F, Gibson TJ (2009) Evidence for the concerted evolution between short linear protein motifs and their flanking regions. PLoS One 4:e6052PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Stein A, Aloy P (2008) Contextual specificity in peptide-mediated protein interactions. PLoS One 3:e2524PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Fuxreiter M, Tompa P (2007) Structural bioinformatics local structural disorder imparts plasticity on linear motifs. Bioinformatics 23:950–956PubMedCrossRefGoogle Scholar
  92. 92.
    Via A, Gould CM, Gemünd C, Gibson TJ, Helmer-Citterich M (2009) A structure filter for the eukaryotic linear motif resource. BMC Bioinform 10:351CrossRefGoogle Scholar
  93. 93.
    Hisamitsu T, Nakamura TY, Wakabayashi S (2012) Na+/H+ exchanger 1 directly binds to calcineurin A and activates downstream NFAT signaling, leading to cardiomyocyte hypertrophy. Mol Cell Biol 32:3265–3280PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Hendus-altenburger R et al (2016) The human Na+/H+ exchanger 1 is a membrane scaffold protein for extracellular signal-regulated kinase 2. BMC Biol 14:31PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Pandey KN (2009) Functional roles of short sequence motifs in the endocytosis of membrane receptors. Front Biosci 14:5339–5360CrossRefGoogle Scholar
  96. 96.
    Reth M (1989) Antigen receptor tail clue. Nature 338:383–384PubMedCrossRefGoogle Scholar
  97. 97.
    Windheim M et al (2016) Sorting motifs in the cytoplasmic tail of the immunomodulatory E3/49K protein of species D adenoviruses modulate cell surface expression and ectodomain shedding. J Biol Chem 291:6796–6812PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Craig HM, Reddy TR, Riggs NL, Dao PP, Guatelli JC (2000) Interactions of HIV-1 Nef with the μ subunits of adaptor protein complexes 1, 2, and 3: role of the dileucine-based sorting motif. Virology 17:9–17CrossRefGoogle Scholar
  99. 99.
    Haft CR et al (1998) Analysis of the juxtamembrane dileucine motif in the insulin receptor. Endocrinology 139:1618–1629PubMedCrossRefGoogle Scholar
  100. 100.
    Shewan AM et al (2000) The cytosolic C-terminus of the glucose transporter GLUT4 contains an acidic cluster endosomal targeting motif distal to the dileucine signal. Biochem J 350:99–107PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Schutze MP, Peterson PA, Jackson MR (1994) An N-terminal double-arginine motif maintains type II membrane proteins in the endoplasmic reticulum. EMBO J 13:1696–1705PubMedPubMedCentralGoogle Scholar
  102. 102.
    Winston JT et al (1999) The SCFβTRCP—ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in I kappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev 13:270–283PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Dinkel H et al (2016) ELM 2016—data update and new functionality of the eukaryotic linear motif resource. Nucleic Acids Res 44:D294–D300PubMedCrossRefGoogle Scholar
  104. 104.
    Zerangue N, Schwappach B, Jan YN, Jan LY (1999) A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane KATP channels. Neuron 22:537–548PubMedCrossRefGoogle Scholar
  105. 105.
    Scott DB, Blanpied TA, Ehlers MD (2003) Coordinated PKA and PKC phosphorylation suppresses RXR-mediated ER retention and regulates the surface delivery of NMDA receptors. Neuropharmacology 45:755–767PubMedCrossRefGoogle Scholar
  106. 106.
    Scott DB, Blanpied TA, Swanson GT, Zhang C, Ehlers MD (2001) An NMDA receptor ER retention signal regulated by phosphorylation and alternative splicing. J Neurosci 21:3063–3072PubMedGoogle Scholar
  107. 107.
    Hong X, Avetisyan M, Ronilo M, Standley S (2015) SAP97 blocks the RXR ER retention signal of NMDA receptor subunit GluN1-3 through its SH3 domain. Biochim Biophys Acta Mol Cell Res 1853:489–499CrossRefGoogle Scholar
  108. 108.
    Shikano S, Li M (2003) Membrane receptor trafficking: evidence of proximal and distal zones conferred by two independent endoplasmic reticulum localization signals. Proc Natl Acad Sci 100:5783–5788PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Meiser A et al (2008) The chemokine receptor CXCR3 Is degraded following internalization and is replenished at the cell surface by de novo synthesis of receptor. J Immunol 180:6713–6724PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Guharoy M, Bhowmick P, Sallam M, Tompa P (2016) Tripartite degrons confer diversity and specificity on regulated protein degradation in the ubiquitin-proteasome system. Nat Commun 7:10239PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Tang W, Pavlish OA, Spiegelman VS, Parkhitko AA, Fuchs SY (2003) Interaction of Epstein-Barr virus latent membrane protein 1 with SCFHOS/beta-TrCP E3 ubiquitin ligase regulates extent of NF-kappaB activation. J Biol Chem 278:48942–48949PubMedCrossRefGoogle Scholar
  112. 112.
    Li Y, Kumar KGK, Tang W, Spiegelman VS, Fuchs SY (2004) Negative regulation of prolactin receptor stability and signaling mediated by SCF(beta-TrCP) E3 ubiquitin ligase. Mol Cell Biol 24:4038–4048PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    da Silva Almeida AC, Strous GJ, van Rossum AGSH (2012) βTrCP controls GH receptor degradation via two different motifs. Mol Endocrinol 26:165–177PubMedCrossRefGoogle Scholar
  114. 114.
    Bezanilla F, Armstrong CM (1977) Inactivation of the sodium channel. I. Sodium current experiments. J Gen Physiol 70:549–566PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Hoshi T, Zagotta WN, Aldrich RW (1990) Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science 250:533–538PubMedCrossRefGoogle Scholar
  116. 116.
    Zhou M, Morais-Cabral JH, Mann S, MacKinnon R (2001) Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors. Nature 411:657–661PubMedCrossRefGoogle Scholar
  117. 117.
    Rettig J et al (1994) Inactivation properties of voltage-gated K+ channels altered by presence of beta-subunit. Nature 369:289–294PubMedCrossRefGoogle Scholar
  118. 118.
    Goldin AL (2003) Mechanisms of sodium channel inactivation. Curr Opin Neurobiol 13:284–290PubMedCrossRefGoogle Scholar
  119. 119.
    Liebovitch LS, Selector LY, Kline RP (1992) Statistical properties predicted by the ball and chain model of channel inactivation. Biophys J 63:1579–1585PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Timpe LC, Peller L (1995) A random flight chain model for the tether of the Shaker K+ channel inactivation domain. Biophys J 69:2415–2418PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Flory PJ, Fox TGJ (1951) Treatment of intrinsic viscosities. J Am Chem Soc 73:1904–1908CrossRefGoogle Scholar
  122. 122.
    Wilkins DK et al (1999) Hydrodynamic radii of native and denatured proteins measured by pulse filed gradient NMR techniques. Biochemistry 38:16424–16431PubMedCrossRefGoogle Scholar
  123. 123.
    Kohn JE et al (2004) Random-coil behavior and the dimensions of chemically unfolded proteins. Proc Natl Acad Sci USA 101:12491–12496PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Das RK, Pappu RV (2013) Conformations of intrinsically disordered proteins are influenced by linear sequence distributions of oppositely charged residues. Proc Natl Acad Sci USA 110:13392–13397PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Müller-Späth S, Soranno A, Hirschfeld V, Hofmann H, Rüegger S (2010) Charge interactions can dominate the dimensions of intrinsically disordered proteins. Proc Natl Acad Sci 107:14609–14614PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Marsh JA, Forman-Kay JD (2010) Sequence determinants of compaction in intrinsically disordered proteins. Biophys J 98:2374–2382CrossRefGoogle Scholar
  127. 127.
    Martin EW et al (2016) Sequence determinants of the conformational properties of an intrinsically disordered protein prior to and upon multisite phosphorylation. J Am Chem Soc 138:15323–15335PubMedCrossRefGoogle Scholar
  128. 128.
    von Heijne G (1989) Control of topology and mode of assembly of a polytopic membrane protein by positively charged residues. Nature 341:189–192CrossRefGoogle Scholar
  129. 129.
    Virkki MT et al (2014) The positive inside rule is stronger when followed by a transmembrane helix. J Mol Biol 426:2982–2991PubMedCrossRefGoogle Scholar
  130. 130.
    Arkhipov A et al (2013) Architecture and membrane interactions of the EGF receptor. Cell 152:557–569PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Endres NF et al (2013) Conformational coupling across the plasma membrane in activation of the EGF receptor. Cell 152:543–556PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Zhang H, Cordoba S-P, Dushek O, Anton van der Merwe P (2011) Basic residues in the T-cell receptor ζ cytoplasmic domain mediate membrane association and modulate signaling. Proc Natl Acad Sci USA 108:19323–19328PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Wang J et al (2002) Lateral sequestration of phosphatidylinositol 4,5-bisphosphate by the basic effector domain of myristoylated alanine-rich C kinase substrate is due to nonspecific electrostatic interactions. J Biol Chem 277:34401–34412PubMedCrossRefGoogle Scholar
  134. 134.
    van der Merwe PA, Zhang H, Cordoba S-P (2012) Why do some t cell receptor cytoplasmic domains associate with the plasma membrane? Front Immunol 3:2011–2013Google Scholar
  135. 135.
    Sigalov AB (2010) Membrane binding of intrinsically disordered proteins: critical importance of an appropriate membrane model. Self Nonself 1:129–132PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Sigalov AB, Hendricks GM (2009) Membrane binding mode of intrinsically disordered cytoplasmic domains of T cell receptor signaling subunits depends on lipid composition. Biochem Biophys Res Commun 389:388–393PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Xu C et al (2008) Regulation of T cell receptor activation by dynamic membrane binding of the CD3? Cytoplasmic tyrosine-based motif. Cell 135:702–713PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Aivazian D, Stern LJ (2000) Phosphorylation of T cell receptor ζ is regulated by a lipid dependency folding transition. Nat Struct Biol 7:1023–1026PubMedCrossRefGoogle Scholar
  139. 139.
    Lopez CA, Sethi A, Goldstein B, Wilson BS, Gnanakaran S (2015) Membrane-mediated regulation of the intrinsically disordered CD3 e cytoplasmic tail of the TCR. Biophys J 108:2481–2491PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Thiel KW, Carpenter G (2007) Epidermal growth factor receptor juxtamembrane region regulates allosteric tyrosine kinase activation. Proc Natl Acad Sci USA 104:19238–19243PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Kim J, Shishido T, Jiang X, Aderem A, McLaughlin S (1994) Phosphorylation, high ionic strength, and calmodulin reverse the binding of MARCKS to phospholipid vesicles. J Biol Chem 269:28214–28219PubMedGoogle Scholar
  142. 142.
    Thelen M, Rosen A, Nairn AC, Aderem A (1991) Regulation by phosphorylations of reversible association of a myristoylated protein kinase C substrate with the plasma membrane. Nature 351:320–322PubMedCrossRefGoogle Scholar
  143. 143.
    Alsop RJ, Schober R, Rheinstadter MC (2016) Swelling of phospholipid membranes by divalent metal ions depends on the location of the ions in the bilayers. Soft Matter 12:6737–6748PubMedCrossRefGoogle Scholar
  144. 144.
    Melcrova A et al (2016) The complex nature of calcium cation interactions with phospholipid bilayers. Sci Rep 6:38035PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    McLaughlin S, Smith SO, Hayman MJ, Murray D (2005) An electrostatic engine model for autoinhibition and activation of the epidermal growth factor receptor (EGFR/ErbB) family. J Gen Physiol 126:41–53PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Lelimousin M, Limongelli V, Sansom MSP (2016) Conformational changes in the epidermal growth factor receptor: role of the transmembrane domain investigated by coarse-grained metadynamics free energy calculations. J Am Chem Soc 138:10611–10622PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    McLaughlin S, Murray D (2005) Plasma membrane phosphoinositide organization by protein electrostatics. Nature 438:605–611PubMedCrossRefGoogle Scholar
  148. 148.
    He L, Hristova K (2012) Consequences of replacing EGFR juxtamembrane domain with an unstructured sequence. Sci Rep 2:854PubMedPubMedCentralGoogle Scholar
  149. 149.
    Hedger G, Sansom MSP, Koldsø H (2015) The juxtamembrane regions of human receptor tyrosine kinases exhibit conserved interaction sites with anionic lipids. Sci Rep 5:9198PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Sengupta D, Chattopadhyay A (2012) Identification of cholesterol binding sites in the serotonin. J Phys Chem B 116:12991–12996PubMedCrossRefGoogle Scholar
  151. 151.
    Björkholm P et al (2014) Identification of novel sphingolipid-binding motifs in mammalian membrane proteins. Biochim Biophys Acta Biomembr 1838:2066–2070CrossRefGoogle Scholar
  152. 152.
    Baier CJ, Fantini J, Barrantes FJ (2011) Disclosure of cholesterol recognition motifs in transmembrane domains of the human nicotinic acetylcholine receptor. Sci Rep 1:69PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Karim CB, Kirby TL, Zhang Z, Nesmelov Y, Thomas DD (2004) Phospholamban structural dynamics in lipid bilayers probed by a spin label rigidly coupled to the peptide backbone. Proc Natl Acad Sci USA 101:14437–14442PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Li J, James ZM, Dong X, Karim CB, Thomas DD (2012) Structural and functional dynamics of an integral membrane protein complex modulated by lipid headgroup charge. J Mol Biol 418:379–389PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Hansen SB, Tao X, MacKinnon R (2011) Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2. Nature 477:495–498PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Deng W, Cho S, Su P-C, Berger BW, Li R (2014) Membrane-enabled dimerization of the intrinsically disordered cytoplasmic domain of ADAM10. Proc Natl Acad Sci USA 111:15987–15992PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    van den Bogaart G et al (2011) Membrane protein sequestering by ionic protein–lipid interactions. Nature 479:552–555PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Liang T et al (2014) Phosphatidylinositol 4,5-biphosphate (PIP2) modulates interaction of syntaxin-1A with sulfonylurea receptor 1 to regulate pancreatic? Cell ATP-sensitive potassium channels. J Biol Chem 289:6028–6040PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Aharonovitz O et al (2000) Intracellular pH regulation by Na(+)/H(+) exchange requires phosphatidylinositol 4,5-bisphosphate. J Cell Biol 150:213–224PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Abu Jawdeh BG et al (2011) Phosphoinositide binding differentially regulates NHE1 Na+/H+ exchanger-dependent proximal tubule cell survival. J Biol Chem 286:42435–42445PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Jiang K et al (2016) PI(4)P promotes phosphorylation and conformational change of smoothened through interaction with its C-terminal tail. PLoS Biol 14:1–26CrossRefGoogle Scholar
  162. 162.
    Martin TFJ (1998) Phosphoinositide lipids as signalling molecules: common themes for signal transduction, cytoskeletal regulation, and membrane trafficking. Annu Rev Cell Dev Biol 14:231–264PubMedCrossRefGoogle Scholar
  163. 163.
    Patwardhan P, Resh MD (2010) Myristoylation and membrane binding regulate c-Src stability and kinase activity. Mol Cell Biol 30:4094–4107PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Rawat A, Nagaraj R (2010) Determinants of membrane association in the SH4 domain of Fyn: roles of N-terminus myristoylation and side-chain thioacylation. Biochim Biophys Acta Biomembr 1798:1854–1863CrossRefGoogle Scholar
  165. 165.
    Rawat A, Harishchandran A, Nagaraj R (2013) Fatty acyl chain-dependent but charge-independent association of the SH4 domain of Lck with lipid membranes. J Biosci 38:63–71PubMedCrossRefGoogle Scholar
  166. 166.
    Bompard G, Martin M, Roy C, Vignon F, Freiss G (2003) Membrane targeting of protein tyrosine phosphatase PTPL1 through its FERM domain via binding to phosphatidylinositol 4,5-biphosphate. J Cell Sci 116:2519–2530PubMedCrossRefGoogle Scholar
  167. 167.
    Feng J, Mertz B (2015) Novel phosphatidylinositol 4,5-bisphosphate binding sites on focal adhesion kinase. PLoS One 10:1–12Google Scholar
  168. 168.
    Hamada K, Shimizu T, Matsui T, Tsukita S, Hakoshima T (2000) Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FERM domain. EMBO J 19:4449–4462PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Sheng R et al (2016) Lipids regulate Lck protein activity through their interactions with the Lck Src homology 2 domain. J Biol Chem 291:17639–17650PubMedCrossRefGoogle Scholar
  170. 170.
    Park M-J et al (2016) SH2 domains serve as lipid-binding modules for pTyr-signaling proteins. Mol Cell 62:7–20PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Yang Y, Igumenova TI (2013) The C-terminal V5 domain of protein kinase C a is intrinsically disordered, with propensity to associate with a membrane mimetic. PLoS One 8:e65699PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Kholodenko BN, Hoek JB, Westerhoff HV (2000) Why cytoplasmic signalling proteins should be recruited to cell membranes. Trends Cell Biol 10:173–178PubMedCrossRefGoogle Scholar
  173. 173.
    Kralt A et al (2015) Intrinsically disordered linker and plasma membrane-binding motif sort Ist2 and Ssy1 to junctions. Traffic 16:135–147PubMedCrossRefGoogle Scholar
  174. 174.
    Khattree N, Ritter LM, Goldberg AFX (2013) Membrane curvature generation by a C-terminal amphipathic helix in peripherin-2/rds, a tetraspanin required for photoreceptor sensory cilium morphogenesis. J Cell Sci 126:4659–4670PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Romero PR et al (2006) Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proc Natl Acad Sci USA 103:8390–8395PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Light S, Sagit R, Sachenkova O, Ekman D, Elofsson A (2013) Protein expansion is primarily due to indels in intrinsically disordered regions. Mol Biol Evol 30:2645–2653PubMedCrossRefGoogle Scholar
  177. 177.
    Light S, Sagit R, Ekman D, Elofsson A (2013) Long indels are disordered: a study of disorder and indels in homologous eukaryotic proteins. Biochim Biophys Acta Proteins Proteom 1834:890–897CrossRefGoogle Scholar
  178. 178.
    Davey NE, Cyert MS, Moses AM (2015) Short linear motifs—ex nihilo evolution of protein regulation. Cell Commun Signal 13:43PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Hendus-Altenburger R, Kragelund BB, Pedersen SF (2014) Structural dynamics and regulation of the mammalian SLC9A family of Na+/H+ exchangers. Curr Top Membr 73:69–148PubMedCrossRefGoogle Scholar
  180. 180.
    Pedersen SF (2004) A novel NHE1 from red blood cells of the winter flounder: regulation by multiple signaling pathways. Adv Exp Med Biol 559:89–98PubMedCrossRefGoogle Scholar
  181. 181.
    Fukura N et al (2010) A membrane-proximal region in the C-terminal tail of NHE7 is required for its distribution in the trans-golgi network, distinct from NHE6 localization at endosomes. J Membr Biol 234:149–158PubMedCrossRefGoogle Scholar
  182. 182.
    Milosavljevic N et al (2014) The intracellular Na+/H+ exchanger NHE7 effects a Na+-coupled, but not K+-coupled proton-loading mechanism in endocytosis. Cell Rep 7:689–696PubMedCrossRefGoogle Scholar
  183. 183.
    Wakabayashi S, Shigekawa M, Pouysségur J (1997) Molecular physiologi of vertebrate Na+/H+ exchangers. Mol Physiol 77:51–74Google Scholar
  184. 184.
    Wakabayashi S, Ikeda T, Iwamoto T, Pouysségur J, Shigekawa M (1997) Calmodulin-binding autoinhibitory domain controls ‘pH-sensing’ in the Na+/H+ exchanger NHE1 through sequence-specific interaction. Biochemistry 36:12854–12861PubMedCrossRefGoogle Scholar
  185. 185.
    Gorbatenko A, Olesen CW, Boedtkjer E, Pedersen SF (2014) Regulation and roles of bicarbonate transporters in cancer. Front Physiol 5:1–15CrossRefGoogle Scholar
  186. 186.
    Boron WF, Chen L, Parker MD (2009) Modular structure of sodium-coupled bicarbonate transporters. J Exp Biol 212:1697–1706PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Liu Y et al (2013) Effects of optional structural elements, including two alternative amino termini and a new splicing cassette IV, on the function of the sodium-bicarbonate cotransporter NBCn1 (SLC4A7). J Physiol 591:4983–5004PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Yang HS et al (2009) Inhibition of rat Na+(-)HCO3 cotransporter (NBCn1) function and expression by the alternative splice domain. Exp Physiol 94:1114–1123PubMedCrossRefGoogle Scholar
  189. 189.
    Choi I, Aalkjaer C, Boulpaep EL, Boron WF (2000) An electroneutral sodium/bicarbonate cotransporter NBCn1 and associated sodium channel. Nature 405:571–575PubMedCrossRefGoogle Scholar
  190. 190.
    Cooper DS et al (2006) The electroneutral sodium/bicarbonate cotransporter containing an amino terminal 123-amino-acid cassette is expressed predominantly in the heart. J Biomed Sci 13:593–595PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Parker MD, Boron WF (2013) The divergence, actions, roles, and relatives of sodium-coupled bicarbonate transporters. Physiol Rev 93:803–959PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Danielsen AA et al (2013) Splice cassette II of Na+, HCO3 cotransporter NBCn1 (slc4a7) interacts with calcineurin a: implications for transporter activity and intracellular pH control during rat artery contractions. J Biol Chem 288:8146–8155PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Holmes KD, Mattar PA, Marsh DR, Weaver LC, Dekaban GA (2001) The N-methyl-d-aspartate receptor splice variant NR1-4 C-terminal domain. J Biol Chem 277:1457–1468PubMedCrossRefGoogle Scholar
  194. 194.
    Horak M, Wenthold RJ (2009) Different roles of C-terminal cassettes in the trafficking of full-length NR1 subunits to the cell surface. J Biol Chem 284:9683–9691PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Standley S, Roche KW, McCallum J, Sans N, Wenthold RJ (2000) PDZ domain suppression of an ER retention signal in NMDA receptor NR1 splice variants. Neuron 28:887–898PubMedCrossRefGoogle Scholar
  196. 196.
    Lunn M-L et al (2007) A unique sorting nexin regulates trafficking of potassium channels via a PDZ domain interaction. Nat Neurosci 10:1249–1259PubMedCrossRefGoogle Scholar
  197. 197.
    Joubert L et al (2004) New sorting nexin (SNX27) and NHERF specifically interact with the 5-HT4a receptor splice variant: roles in receptor targeting. J Cell Sci 117:5367–5379PubMedCrossRefGoogle Scholar
  198. 198.
    Kamiguchi H, Lemmon V (1998) A neuronal form of the cell adhesion molecule L1 contains a tyrosine-based signal required for sorting to the axonal growth cone. J Neurosci 18:3749–3756PubMedPubMedCentralGoogle Scholar
  199. 199.
    Qazi AM, Tsai-Morris C-H, Dufau ML (2006) Ligand-independent homo-and heterodimerization of human prolactin receptor variants: inhibitory action of the short forms by heterodimerization. Mol Endocrinol 20:1912–1923PubMedCrossRefGoogle Scholar
  200. 200.
    Guiramand J, Montmayeur J-P, Ceraline J, Bhatia M, Borrelli E (1995) Alternative splicing of the dopamine D2 receptor directs specificity of coupling to G-proteins. J Biol Chem 270:7354–7358PubMedCrossRefGoogle Scholar
  201. 201.
    Usiello A et al (2000) Distinct functions of the two isoforms of dopamine D2 receptors. Nature 408:199–203PubMedCrossRefGoogle Scholar
  202. 202.
    Radl D, De Mei C, Chen E, Lee H, Borrelli E (2013) Each individual isoform of the dopamine D2 receptor protects from lactotroph hyperplasia. Mol Endocrinol 27:953–965PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Nishikawa I et al (2010) Computational prediction of O-linked glycosylation sites that preferentially map on intrinsically disordered regions of extracellular proteins. Int J Mol Sci 11:4991–5008PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Qiu S et al (2009) An endoplasmic reticulum retention signal located in the extracellular amino-terminal domain of the NR2A subunit of N-methyl-d-aspartate receptors. J Biol Chem 284:20285–20298PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Bonnon C et al (2007) PGY repeats and N-glycans govern the trafficking of paranodin and its selective association with contactin. Mol Biol Cell 18:229–241PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Mysling S et al (2016) The acidic domain of the endothelial membrane protein GPIHBP1 stabilizes lipoprotein lipase activity by preventing unfolding of its catalytic domain. Elife 5:e12095PubMedPubMedCentralGoogle Scholar
  207. 207.
    Mysling S et al (2016) ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and that unfolding is counteracted by GPIHBP1. Elife 5:e20958PubMedPubMedCentralGoogle Scholar
  208. 208.
    König I et al (2015) Single-molecule spectroscopy of protein conformational dynamics in live eukaryotic cells. Nat Methods 12:773–779PubMedCrossRefGoogle Scholar
  209. 209.
    Sustarsic M, Kapanidis AN (2015) Taking the ruler to the jungle: single-molecule FRET for understanding biomolecular structure and dynamics in live cells. Curr Opin Struct Biol 34:52–59PubMedCrossRefGoogle Scholar
  210. 210.
    Krogh A, Larsson B, von Heijne G, Sonnhammer ELL (2001) Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. J Mol Biol 305:567–580PubMedCrossRefGoogle Scholar
  211. 211.
    Karakas E, Furukawa H (2014) Crystal structure of a heterotetrameric NMDA receptor ion channel. Science 344:992–997PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Ward JJ, McGuffin LJ, Bryson K, Buxton BF, Jones DT (2004) The DISOPRED server for the prediction of protein disorder. Bioinformatics 20:2138–2139PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Aarhus Institute of Advanced Studies (AIAS)Aarhus UniversityAarhusDenmark
  2. 2.Department of Molecular Biology and GeneticsAarhus UniversityAarhusDenmark
  3. 3.Interdisciplinary Nanoscience Center (iNANO)Aarhus UniversityAarhusDenmark
  4. 4.The Danish Research Institute of Translational Neuroscience (DANDRITE)AarhusDenmark
  5. 5.Structural Biology and NMR Laboratory and The Linderstrøm-Lang Centre for Protein Science, Department of BiologyUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations