Abstract
Based on ubiquitous presence of large ionic motifs and clusters in proteins involved in gene transcription and protein synthesis, we analyzed the distribution of ionizable sidechains in a broad selection of proteins with regulatory, metabolic, structural and adhesive functions, in agonist, antagonist, toxin and antimicrobial peptides, and in self-excising inteins and intron-derived proteins and sequence constructs. All tested groups, regardless of taxa or sequence size, show considerable segregation of ionizable sidechains into same type charge (homoionic) tracts. These segments in most cases exceed half of the sequence length and comprise more than two-thirds of all ionizable sidechains. This distribution of ionic residues apparently reflects a fundamental advantage of sorted electrostatic contacts in association of sequence elements within and between polypeptides, as well as in interaction with polynucleotides. While large ionic densities are encountered in highly interactive proteins, the average ionic density in most sets does not change appreciably with size of the homoionic segments, which supports the segregation as a modular feature favoring association.
Similar content being viewed by others
Abbreviations
- aa:
-
Amino acid (residue)
- ec1:
-
First extracellular domain
- GPCR:
-
G-protein coupling receptor
- ic3:
-
Third intracellular domain
- ic4:
-
Fourth intracellular domain
- NLM:
-
US National Library of Medicine
- u-p:
-
UniProtein database
References
Allan J, Harborne N, Rau DC, Gould H (1982) Participation of core histone “tails” in the stabilization of the chromatin solenoid. J Cell Biol 93:285–297
Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215:403–410
Annilo T, Karis A, Hoth S, Rikk T, Kruppa J, Metspalu A (1998) Nuclear import and nucleolar accumulation of the human ribosomal protein S7 depends on both a minimal nuclear localization sequence and an adjacent basic region. Biochem Biophys Res Commun 249:759–766
Anraku K, Inoue T, Sugimoto K, Kudo K, Okamoto Y, Morii T, Mori Y, Otsuka M (2011) Design and synthesis of biotinylated inositol 1,3,4,5-tetrakisphosphate targeting Grp1 pleckstrin homology domain. Bioorg Med Chem 19:6833–6841
Ausiello DA, Stow JL, Cantiello HF, de Almeida JB, Benos DJ (1992) Purified epithelial Na+ channel complex contains the pertussis toxin-sensitive G alpha i-3 protein. J Biol Chem 267:4759–4765
Baker AM, Fu Q, Hayward W, Victoria S, Pedroso IM, Lindsay SM, Fletcher TM (2011) The telomere binding protein TRF2 induces chromatin compaction. PLoS ONE 6:e19124
Balhorn R (2007) The protamine family of sperm nuclear proteins. Genome Biol 8:227
Ballesteros JA, Shi L, Javitch JA (2001) Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors. Mol Pharmacol 60:1–19
Ban C, Ramakrishnan B, Ling KY, Kung C, Sundaralingam M (1994) Structure of the recombinant Paramecium tetraurelia calmodulin at 1.68 A resolution. Acta Crystallogr D Biol Crystallogr 50:50–63
Baneres JL, Parello J (2003) Structure-based analysis of GPCR function: evidence for a novel pentameric assembly between the dimeric leukotriene B4 receptor BLT1 and the G-protein. J Mol Biol 329:815–829
Banerjee A, MacKinnon R (2008) Inferred motions of the S3a helix during voltage-dependent K + channel gating. J Mol Biol 381:569–580
Baron V, Alengrin F, Van Obberghen E (1998) Dynamin associates with Src-Homology Collagen (Shc) and becomes tyrosine phosphorylated in response to insulin. Endocrinology 139:3034–3037
Barret C, Roy C, Montcourrier P, Mangeat P, Niggli V (2000) Mutagenesis of the phosphatidylinositol 4,5-bisphosphate (PIP(2)) binding site in the NH(2)-terminal domain of ezrin correlates with its altered cellular distribution. J Cell Biol 151:1067–1080
Biddlecome GH, Berstein G, Ross EM (1996) Regulation of phospholipase C-beta1 by Gq and m1 muscarinic cholinergic receptor. Steady-state balance of receptor-mediated activation and GTPase-activating protein-promoted deactivation. J Biol Chem 271:7999–8007
Birbach A, Bailey ST, Ghosh S, Schmid JA (2004) Cytosolic, nuclear and nucleolar localization signals determine subcellular distribution and activity of the NF-kappaB inducing kinase NIK. J Cell Sci 117:3615–3624
Brennan CM, Gallouzi IE, Steitz JA (2000) Protein ligands to HuR modulate its interaction with target mRNAs in vivo. J Cell Biol 151:1–14
Bruno ME, West RB, Schneeman TA, Bresnick EH, Kaetzel CS (2004) Upstream stimulatory factor but not c-Myc enhances transcription of the human polymeric immunoglobulin receptor gene. Mol Immunol 40:695–708
Bugatti A, Chiodelli P, Rosenbluh J, Loyter A, Rusnati M (2010) BSA conjugates bearing multiple copies of the basic domain of HIV-1 Tat: Prototype for the development of multitarget inhibitors of extracellular Tat. Antiviral Res 87:30–39
Choi JH, Murray JW, Wolkoff AW (2012) PDZK1 binding and serine phosphorylation reg2012ulate subcellular trafficking of organic anion transport protein 1a1. Am J Physiol Gastrointest Liver Physiol 300:G384–G393
Chou PY, Fasman GD (1974) Prediction of protein conformation. Biochemistry 13:222–245
Cohen SL, Ferre-D’Amare AR, Burley SK, Chait BT (1995) Probing the solution structure of the DNA-binding protein Max by a combination of proteolysis and mass spectrometry. Protein Sci 4:1088–1099
Cokol M, Nair R, Rost B (2000) Finding nuclear localization signals. EMBO Rep 1:411–415
Creancier L, Prats H, Zanibellato C, Amalric F, Bugler B (1993) Determination of the functional domains involved in nucleolar targeting of nucleolin. Mol Biol Cell 4:1239–1250
Dang CV, Lee WM (1989) Nuclear and nucleolar targeting sequences of c-erb-A, c-myb, N-myc, p53, HSP70, and HIV tat proteins. J Biol Chem 264:18019–18023
Dautzenberg FM, Neysari S (2005) Irreversible binding kinetics of neuropeptide Y ligands to Y2 but not to Y1 and Y5 receptors. Pharmacology 75:21–29
Dessauer CW, Tesmer JJ, Sprang SR, Gilman AG (1998) Identification of a Gialpha binding site on type V adenylyl cyclase. J Biol Chem 273:25831–25839
Doyle A, Crosby SR, Burton DR, Lilley F, Murphy MF (2010) Actin bundling and polymerisation properties of eukaryotic elongation factor 1 alpha (eEF1A), histone H2A–H2B and lysozyme in vitro. J Struct Biol 176:370–378
Elleuche S, Poggeler S (2011) Inteins, valuable genetic elements in molecular biology and biotechnology. Appl Microbiol Biotechnol 87:479–489
Fries M, Chauhan HJ, Domingo GJ, Jung HI, Perham RN (2003) Site-directed mutagenesis of a loop at the active site of E1 (alpha2beta2) of the pyruvate dehydrogenase complex. A possible common sequence motif. Eur J Biochem 270:861–870
Gibb EA, Edgell DR (2011) Better late than early: delayed translation of intron-encoded endonuclease I-TevI is required for efficient splicing of its host group I intron. Mol Microbiol 78:35–46
Gifford JL, Walsh MP, Vogel HJ (2007) Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs. Biochem J 405:199–221
Gogarten JP, Hilario E (2006) Inteins, introns, and homing endonucleases: recent revelations about the life cycle of parasitic genetic elements. BMC Evol Biol 6:94
Grabarek Z (2006) Structural basis for diversity of the EF-hand calcium-binding proteins. J Mol Biol 359:509–525
GuhaThakurta D, Draper DE (2000) Contributions of basic residues to ribosomal protein L11 recognition of RNA. J Mol Biol 295:569–580
Hallett MA, Lo HS, Bender A (2002) Probing the importance and potential roles of the binding of the PH-domain protein Boi1 to acidic phospholipids. BMC Cell Biol 3:16
Hanover JA, Love DC, DeAngelis N, O’Kane ME, Lima-Miranda R, Schulz T, Yen YM, Johnson RC, Prinz WA (2007) The High Mobility Group Box Transcription Factor Nhp6Ap enters the nucleus by a calmodulin-dependent, Ran-independent pathway. J Biol Chem 282:33743–33751
Herzog H, Darby K, Ball H, Hort Y, Beck-Sickinger A, Shine J (1997) Overlapping gene structure of the human neuropeptide Y receptor subtypes Y1 and Y5 suggests coordinate transcriptional regulation. Genomics 41:315–319
Hilal-Dandan R, Villegas S, Gonzalez A, Brunton LL (1997) The quasi-irreversible nature of endothelin binding and G protein-linked signaling in cardiac myocytes. J Pharmacol Exp Ther 281:267–273
Hoeffler JP, Meyer TE, Yun Y, Jameson JL, Habener JF (1988) Cyclic AMP-responsive DNA-binding protein: structure based on a cloned placental cDNA. Science 242:1430–1433
Hong M, Su Y (2011) Structure and dynamics of cationic membrane peptides and proteins: insights from solid-state NMR. Protein Sci 20:641–655
Houmani JL, Ruf IK (2009) Clusters of basic amino acids contribute to RNA binding and nucleolar localization of ribosomal protein L22. PLoS ONE 4:e5306
Ikeda M, Arai M, Lao DM, Shimizu T (2002) Transmembrane topology prediction methods: a re-assessment and improvement by a consensus method using a dataset of experimentally-characterized transmembrane topologies. In Silico Biol 2:19–33
Jung KC, Rhee HS, Park CH, Yang CH (2005) Determination of the dissociation constants for recombinant c-Myc, Max, and DNA complexes: the inhibitory effect of linoleic acid on the DNA-binding step. Biochem Biophys Res Commun 334:269–275
Jung KH, Spudich JL (1996) Protonatable residues at the cytoplasmic end of transmembrane helix-2 in the signal transducer HtrI control photochemistry and function of sensory rhodopsin I. Proc Natl Acad Sci USA 93:6557–6561
Klasse PJ, Rosenkilde MM, Signoret N, Pelchen-Matthews A, Schwartz TW, Marsh M (1999) CD4-Chemokine receptor hybrids in human immunodeficiency virus type 1 infection. J Virol 73:7453–7466
Komeiji Y, Uebayasi M, Yamato I (1994) Molecular dynamics simulations of trp apo- and holorepressors: domain structure and ligand-protein interaction. Proteins 20:248–258
Krebs D, Dahmani B, Monnot M, Mauffret O, Troalen F, Fermandjian S (1996) Dissection of the basic subdomain of the c-Jun oncoprotein: a structural analysis of two peptide fragments by CD, Fourier-transform infrared and NMR. Eur J Biochem 235:699–712
Lee JC, Wang GX, Schickling O, Peter ME (2005) Fusing DEDD with ubiquitin changes its intracellular localization and apoptotic potential. Apoptosis 10:1483–1495
MacKichan ML, Logeat F, Israel A (1996) Phosphorylation of p105 PEST sequence via a redox-insensitive pathway up-regulates processing of p50 NF-kappaB. J Biol Chem 271:6084–6091
Malesevic M, Poehlmann A, Hernandez Alvarez B, Diessner A, Trager M, Rahfeld JU, Jahreis G, Liebscher S, Bordusa F, Fischer G, Lucke C (2011) The protein-free IANUS peptide array uncovers interaction sites between Escherichia coli parvulin 10 and alkyl hydroperoxide reductase. Biochemistry 49:8626–8635
McPherson PS, Czernik AJ, Chilcote TJ, Onofri F, Benfenati F, Greengard P, Schlessinger J, De Camilli P (1994) Interaction of Grb2 via its Src homology 3 domains with synaptic proteins including synapsin I. Proc Natl Acad Sci USA 91:6486–6490
Meskauskas A, Dinman JD (2010) A molecular clamp ensures allosteric coordination of peptidyltransfer and ligand binding to the ribosomal A-site. Nucleic Acids Res 38:7800–7813
Mitchell JB, Thornton JM, Singh J, Price SL (1992) Towards an understanding of the arginine-aspartate interaction. J Mol Biol 226:251–262
Nakagawa H, Umadome H, Miyazaki S, Tanaka K, Nishimura K, Komori M, Matsuo S (2011) ER-resident Gi2 protein controls sar1 translocation onto the ER during budding of transport vesicles. J Cell Biochem 112:2250–2256
Neumann F, Hemmerich P, von Mikecz A, Peter HH, Krawinkel U (1995) Human ribosomal protein L7 inhibits cell-free translation in reticulocyte lysates and affects the expression of nuclear proteins upon stable transfection into Jurkat T-lymphoma cells. Nucleic Acids Res 23:195–202
Oksche A, Boese G, Horstmeyer A, Furkert J, Beyermann M, Bienert M, Rosenthal W (2000) Late endosomal/lysosomal targeting and lack of recycling of the ligand-occupied endothelin B receptor. Mol Pharmacol 57:1104–1113
Olivares-Reyes JA, Smith RD, Hunyady L, Shah BH, Catt KJ (2001) Agonist-induced signaling, desensitization, and internalization of a phosphorylation-deficient AT1A angiotensin receptor. J Biol Chem 276:37761–37768
Palau J, Climent F, Aviles FJ, Morros A, Soliva M (1977) Interactions of histones and histone peptides with DNA Thermal denaturation and solubility studies. Biochim Biophys Acta 476:108–121
Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289:739–745
Palombella VJ, Rando OJ, Goldberg AL, Maniatis T (1994) The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 78:773–785
Parker MS, Lundell I, Parker SL (2002) Pancreatic polypeptide receptors: affinity, sodium sensitivity and stability of agonist binding. Peptides 23:291–302
Parker MS, Park EA, Sallee FR, Parker SL (2011) Two intracellular helices of G-protein coupling receptors could generally support oligomerization and coupling with transducers. Amino Acids 40:261–268
Parker MS, Sah R, Balasubramaniam A, Sallee FR, Zerbe O, Parker SL (2011) Non-specific binding and general cross-reactivity of Y receptor agonists are correlated and should importantly depend on their acidic sectors. Peptides 32:258–265
Parker MW, Tucker AD, Tsernoglou D, Pattus F (1990) Insights into membrane insertion based on studies of colicins. Trends Biochem Sci 15:126–129
Parker SL, Parker MS, Wong YY, Sah R, Balasubramaniam A, Sallee F (2008) Importance of a N-terminal aspartate in the internalization of the neuropeptide Y Y2 receptor. Eur J Pharmacol 594:26–31
Pearson WR (1990) Rapid and sensitive sequence comparison with FASTP and FASTA. Methods Enzymol 183:63–98
Pearson WR (2000) Flexible sequence similarity searching with the FASTA3 program package. Methods Mol Biol 132:185–219
Perissi V, Aggarwal A, Glass CK, Rose DW, Rosenfeld MG (2004) A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors. Cell 116:511–526
Pollastri G, Martin AJ, Mooney C, Vullo A (2007) Accurate prediction of protein secondary structure and solvent accessibility by consensus combiners of sequence and structure information. BMC Bioinform 8:201
Romanelli MG, Tato L, Lorenzi P, Morandi C (2003) Nuclear localization domains in human thyroid transcription factor 2. Biochim Biophys Acta 1643:55–64
Romano RA, Kannan N, Kornev AP, Allison CJ, Taylor SS (2009) A chimeric mechanism for polyvalent trans-phosphorylation of PKA by PDK1. Protein Sci 18:1486–1497
Rosenbaum S, Kreft S, Etich J, Frie C, Stermann J, Grskovic I, Frey B, Mielenz D, Poschl E, Gaipl U, Paulsson M, Brachvogel B (2011) Identification of novel binding partners (annexins) for the cell death signal phosphatidylserine and definition of their recognition motif. J Biol Chem 286:5708–5716
Rosenkilde MM, Schwartz TW (2004) The chemokine system—a major regulator of angiogenesis in health and disease. Apmis 112:481–495
Rosner M, Fuchs C, Dolznig H, Hengstschlager M (2011) Different cytoplasmic/nuclear distribution of S6 protein phosphorylated at S240/244 and S235/236. Amino Acids 40:595–600
Rusnati M, Tanghetti E, Urbinati C, Tulipano G, Marchesini S, Ziche M, Presta M (1999) Interaction of fibroblast growth factor-2 (FGF-2) with free gangliosides: biochemical characterization and biological consequences in endothelial cell cultures. Mol Biol Cell 10:313–327
Saudek V, Pasley HS, Gibson T, Gausepohl H, Frank R, Pastore A (1991) Solution structure of the basic region from the transcriptional activator GCN4. Biochemistry 30:1310–1317
Shibata Y, Muramatsu T, Hirai M, Inui T, Kimura T, Saito H, McCormick LM, Bu G, Kadomatsu K (2002) Nuclear targeting by the growth factor midkine. Mol Cell Biol 22:6788–6796
Singh RN, Saldanha RJ, D’Souza LM, Lambowitz AM (2002) Binding of a group II intron-encoded reverse transcriptase/maturase to its high affinity intron RNA binding site involves sequence-specific recognition and autoregulates translation. J Mol Biol 318:287–303
Sonnhammer EL, von Heijne G, Krogh A (1998) A hidden Markov model for predicting transmembrane helices in protein sequences. In: Glasgow et al. J (eds) Proceedings of the sixth international conference on intelligent systems for molecular biology, vol 1. AAAI Press, Menlo Park, pp 175–182
Sperling R, Koster AJ, Melamed-Bessudo C, Rubinstein A, Angenitzki M, Berkovitch-Yellin Z, Sperling J (1997) Three-dimensional image reconstruction of large nuclear RNP (lnRNP) particles by automated electron tomography. J Mol Biol 267:570–583
Springael JY, Le Minh PN, Urizar E, Costagliola S, Vassart G, Parmentier M (2006) Allosteric modulation of binding properties between units of chemokine receptor homo- and hetero-oligomers. Mol Pharmacol 69:1652–1661
Sunahara RK, Dessauer CW, Whisnant RE, Kleuss C, Gilman AG (1997) Interaction of Gsalpha with the cytosolic domains of mammalian adenylyl cyclase. J Biol Chem 272:22265–22271
Sunahara RK, Tesmer JJ, Gilman AG, Sprang SR (1997) Crystal structure of the adenylyl cyclase activator Gsalpha. Science 278:1943–1947
Thiele A, Krentzlin K, Erdmann F, Rauh D, Hause G, Zerweck J, Kilka S, Posel S, Fischer G, Schutkowski M, Weiwad M (2011) Parvulin 17 promotes microtubule assembly by its peptidyl-prolyl cis/trans isomerase activity. J Mol Biol 411:896–909
Trub T, Frantz JD, Miyazaki M, Band H, Shoelson SE (1997) The role of a lymphoid-restricted, Grb2-like SH3-SH2-SH3 protein in T cell receptor signaling. J Biol Chem 272:894–902
Uno Y, Furihata T, Abe H, Yoshida R, Shinozaki K, Yamaguchi-Shinozaki K (2000) Arabidopsis basic leucine zipper transcription factors involved in an abscisic acid-dependent signal transduction pathway under drought and high-salinity conditions. Proc Natl Acad Sci USA 97:11632–11637
Vanni S, Neri M, Tavernelli I, Rothlisberger U (2011) A conserved protonation-induced switch can trigger “ionic-lock” formation in adrenergic receptors. J Mol Biol 397:1339–1349
Wang X, McLachlan J, Zamore PD, Hall TM (2002) Modular recognition of RNA by a human pumilio-homology domain. Cell 110:501–512
Weiss MA, Ellenberger T, Wobbe CR, Lee JP, Harrison SC, Struhl K (1990) Folding transition in the DNA-binding domain of GCN4 on specific binding to DNA. Nature 347:575–578
Weng X, Luecke H, Song IS, Kang DS, Kim SH, Huber R (1993) Crystal structure of human annexin I at 2.5 A resolution. Protein Sci 2:448–458
Wiedlocha A, Sorensen V (2004) Signaling, internalization, and intracellular activity of fibroblast growth factor. Curr Top Microbiol Immunol 286:45–79
Wolf A, Krause-Gruszczynska M, Birkenmeier O, Ostareck-Lederer A, Huttelmaier S, Hatzfeld M (2012) Plakophilin 1 stimulates translation by promoting eIF4A1 activity. J Cell Biol 188:463–471
Xu D, Popov N, Hou M, Wang Q, Bjorkholm M, Gruber A, Menkel AR, Henriksson M (2001) Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells. Proc Natl Acad Sci U S A 98:3826–3831
Yamamoto Y, Sono D, Sokawa Y (2000) Effects of specific mutations in active site motifs of 2′,5′-oligoadenylate synthetase on enzymatic activity. J Interferon Cytokine Res 20:337–344
Yasuda D, Okuno T, Yokomizo T, Hori T, Hirota N, Hashidate T, Miyano M, Shimizu T, Nakamura M (2009) Helix 8 of leukotriene B4 type-2 receptor is required for the folding to pass the quality control in the endoplasmic reticulum. Faseb J 23:1470–1481
Zhou N, Zhang X, Fan X, Argyris E, Fang J, Acheampong E, DuBois GC, Pomerantz RJ (2003) The N-terminal domain of APJ, a CNS-based coreceptor for HIV-1, is essential for its receptor function and coreceptor activity. Virology 317:84–94
Zou P, Pinotsis N, Lange S, Song YH, Popov A, Mavridis I, Mayans OM, Gautel M, Wilmanns M (2006) Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk. Nature 439:229–233
Zurita AR, Birnbaumer L (2008) The same mutation in Gsalpha and transducin alpha reveals behavioral differences between these highly homologous G protein alpha-subunits. Proc Natl Acad Sci USA 105:2363–2368
Acknowledgments
This work was partly supported by the U.S. National Institutes of Health grants R01-HD13703 and R01 HD-20074, and also in part by grants from Shriners Hospital for Children, #8570 and #86400 and a Department of Veteran Affairs Grant, 1I01BX000263 (to A.B.).
Conflict of interest
The authors declare no conflicts of interest related to subjects of this study.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Parker, M.S., Balasubramaniam, A. & Parker, S.L. On the segregation of protein ionic residues by charge type. Amino Acids 43, 2231–2247 (2012). https://doi.org/10.1007/s00726-012-1418-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-012-1418-4