Biophysical Reviews

, Volume 10, Issue 2, pp 421–433 | Cite as

“Multiple partial recognitions in dynamic equilibrium” in the binding sites of proteins form the molecular basis of promiscuous recognition of structurally diverse ligands

Review
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Abstract

Promiscuous recognition of ligands by proteins is as important as strict recognition in numerous biological processes. In living cells, many short, linear amino acid motifs function as targeting signals in proteins to specify the final destination of the protein transport. In general, the target signal is defined by a consensus sequence containing wild-characters, and hence represented by diverse amino acid sequences. The classical lock-and-key or induced-fit/conformational selection mechanism may not cover all aspects of the promiscuous recognition. On the basis of our crystallographic and NMR studies on the mitochondrial Tom20 protein–presequence interaction, we proposed a new hypothetical mechanism based on “a rapid equilibrium of multiple states with partial recognitions”. This dynamic, multiple recognition mode enables the Tom20 receptor to recognize diverse mitochondrial presequences with nearly equal affinities. The plant Tom20 is evolutionally unrelated to the animal Tom20 in our study, but is a functional homolog of the animal/fungal Tom20. NMR studies by another research group revealed that the presequence binding by the plant Tom20 was not fully explained by simple interaction modes, suggesting the presence of a similar dynamic, multiple recognition mode. Circumstantial evidence also suggested that similar dynamic mechanisms may be applicable to other promiscuous recognitions of signal peptides by the SRP54/Ffh and SecA proteins.

Keywords

Mitochondrial presequence Promiscuous recognition Signal sequence Targeting signal Tom20 

Abbreviations

ER

Endoplasmic reticulum

MD

Molecular dynamics

MPRIDE

Multiple partial recognition in dynamic equilibrium

NOE

Nuclear Overhauser effect

TIM

Translocase of the inner mitochondrial membrane

TOM

Translocase of the outer mitochondrial membrane

Tom20

20-kDa subunit of the TOM complex

PRE

Paramagnetic relaxation enhancement

Notes

Acknowledgements

This review is the achievement of our long-term research project for more than 20 years, conducted at the Biomolecular Engineering Research Institute with Drs. Yoshito Abe and Takanori Muto, and at the Medical Institute of Bioregulation, Kyushu University, with Drs. Takayuki Obita, Takashi Saitoh, Toyoyuki Ose, Nobuo Maita, Reiko Kojima, Mayumi Igura, Rei Matsuoka, and Atsushi Shimada, Mr. Keisei Izumi, and Ms. Han Xiling. We thank Professor Toshiya Endo (Kyoto Sangyo University) for fruitful discussions on the biochemical functions of the TOM and TIM proteins, and Drs. Yasuaki Komuro and Yuji Sugita (RIKEN Advanced Science Institute), and Dr. Naoyuki Miyashita (RIKEN Quantitative Biology Center) for their MD calculations and stimulating discussions.

Compliance with ethical standards

Conflict of interest

Daisuke Kohda declares that the author has no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by the author.

References

  1. Abe Y et al (2000) Structural basis of presequence recognition by the mitochondrial protein import receptor Tom20. Cell 100:551–560CrossRefPubMedGoogle Scholar
  2. Ast J, Stiebler AC, Freitag J, Bolker M (2013) Dual targeting of peroxisomal proteins. Front Physiol 4:297.  https://doi.org/10.3389/fphys.2013.00297 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Baker MJ, Frazier AE, Gulbis JM, Ryan MT (2007) Mitochondrial protein-import machinery: correlating structure with function. Trends Cell Biol 17:456–464.  https://doi.org/10.1016/j.tcb.2007.07.010 CrossRefPubMedGoogle Scholar
  4. Banfield DK (2011) Mechanisms of protein retention in the Golgi. Cold Spring Harb Perspect Biol 3:a005264.  https://doi.org/10.1101/cshperspect.a005264 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bonifacino JS, Traub LM (2003) Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem 72:395–447.  https://doi.org/10.1146/annurev.biochem.72.121801.161800 CrossRefPubMedGoogle Scholar
  6. Braulke T, Bonifacino JS (2009) Sorting of lysosomal proteins. Biochim Biophys Acta 1793:605–614.  https://doi.org/10.1016/j.bbamcr.2008.10.016 CrossRefPubMedGoogle Scholar
  7. Brix J, Dietmeier K, Pfanner N (1997) Differential recognition of preproteins by the purified cytosolic domains of the mitochondrial import receptors Tom20, Tom22, and Tom70. J Biol Chem 272:20730–20735CrossRefPubMedGoogle Scholar
  8. Capitani M, Sallese M (2009) The KDEL receptor: new functions for an old protein. FEBS Lett 583:3863–3871.  https://doi.org/10.1016/j.febslet.2009.10.053 CrossRefPubMedGoogle Scholar
  9. Carrie C, Giraud E, Whelan J (2009) Protein transport in organelles: dual targeting of proteins to mitochondria and chloroplasts. FEBS J 276:1187–1195.  https://doi.org/10.1111/j.1742-4658.2009.06876.x CrossRefPubMedGoogle Scholar
  10. Chakraborty P, Di Cera E (2017) Induced fit is a special case of conformational selection. Biochemistry 56:2853–2859.  https://doi.org/10.1021/acs.biochem.7b00340 CrossRefPubMedGoogle Scholar
  11. Changeux JP, Edelstein S (2011) Conformational selection or induced fit? 50 years of debate resolved. F1000 Biol Reprod 3:19.  https://doi.org/10.3410/B3-19 Google Scholar
  12. Chotewutmontri P, Holbrook K, Bruce BD (2017) Plastid protein targeting: preprotein recognition and translocation. Int Rev Cell Mol Biol 330:227–294.  https://doi.org/10.1016/bs.ircmb.2016.09.006 CrossRefPubMedGoogle Scholar
  13. Clerico EM, Maki JL, Gierasch LM (2008) Use of synthetic signal sequences to explore the protein export machinery. Biopolymers 90:307–319.  https://doi.org/10.1002/bip.20856 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Csermely P, Palotai R, Nussinov R (2010) Induced fit, conformational selection and independent dynamic segments: an extended view of binding events. Trends Biochem Sci 35:539–546.  https://doi.org/10.1016/j.tibs.2010.04.009 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Darimont BD et al (1998) Structure and specificity of nuclear receptor–coactivator interactions. Genes Dev 12:3343–3356CrossRefPubMedPubMedCentralGoogle Scholar
  16. Endo T, Kohda D (2002) Functions of outer membrane receptors in mitochondrial protein import. Biochim Biophys Acta 1592:3–14CrossRefPubMedGoogle Scholar
  17. Endo T, Yamamoto H, Esaki M (2003) Functional cooperation and separation of translocators in protein import into mitochondria, the double-membrane bounded organelles. J Cell Sci 116:3259–3267.  https://doi.org/10.1242/jcs.00667 CrossRefPubMedGoogle Scholar
  18. Fischer E (1894) Einfluss der Configuration auf die Wirkung der Enzyme. Ber Dtsch Chem Ges 27:2984–2993Google Scholar
  19. Gelis I et al (2007) Structural basis for signal-sequence recognition by the translocase motor SecA as determined by NMR. Cell 131:756–769.  https://doi.org/10.1016/j.cell.2007.09.039 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Gianni S, Dogan J, Jemth P (2014) Distinguishing induced fit from conformational selection. Biophys Chem 189:33–39.  https://doi.org/10.1016/j.bpc.2014.03.003 CrossRefPubMedGoogle Scholar
  21. Greives N, Zhou HX (2014) Both protein dynamics and ligand concentration can shift the binding mechanism between conformational selection and induced fit. Proc Natl Acad Sci U S A 111:10197–10202.  https://doi.org/10.1073/pnas.1407545111 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hainzl T, Huang S, Merilainen G, Brannstrom K, Sauer-Eriksson AE (2011) Structural basis of signal-sequence recognition by the signal recognition particle. Nat Struct Mol Biol 18:389–391.  https://doi.org/10.1038/nsmb.1994 CrossRefPubMedGoogle Scholar
  23. Hainzl T, Sauer-Eriksson AE (2015) Signal-sequence induced conformational changes in the signal recognition particle. Nat Commun 6:7163.  https://doi.org/10.1038/ncomms8163 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hammes GG, Chang YC, Oas TG (2009) Conformational selection or induced fit: a flux description of reaction mechanism. Proc Natl Acad Sci U S A 106:13737–13741.  https://doi.org/10.1073/pnas.0907195106 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Heery DM, Kalkhoven E, Hoare S, Parker MG (1997) A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387:733–736.  https://doi.org/10.1038/42750 CrossRefPubMedGoogle Scholar
  26. Janda CY, Li J, Oubridge C, Hernandez H, Robinson CV, Nagai K (2010) Recognition of a signal peptide by the signal recognition particle. Nature 465:507–510.  https://doi.org/10.1038/nature08870 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Jolliffe NA, Craddock CP, Frigerio L (2005) Pathways for protein transport to seed storage vacuoles. Biochem Soc Trans 33:1016–1018.  https://doi.org/10.1042/BST20051016 CrossRefPubMedGoogle Scholar
  28. Kim YH, Han ME, Oh SO (2017) The molecular mechanism for nuclear transport and its application. Anat Cell Biol 50:77–85.  https://doi.org/10.5115/acb.2017.50.2.77 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Komuro Y, Miyashita N, Mori T, Muneyuki E, Saitoh T, Kohda D, Sugita Y (2013) Energetics of the presequence-binding poses in mitochondrial protein import through Tom20. J Phys Chem B 117:2864–2871.  https://doi.org/10.1021/jp400113e CrossRefPubMedGoogle Scholar
  30. Koshland DE (1958) Application of a theory of enzyme specificity to protein synthesis. Proc Natl Acad Sci U S A 44:98–104CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kunze M, Berger J (2015) The similarity between N-terminal targeting signals for protein import into different organelles and its evolutionary relevance. Front Physiol 6:259.  https://doi.org/10.3389/fphys.2015.00259 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Likic VA et al (2005) Patterns that define the four domains conserved in known and novel isoforms of the protein import receptor Tom20. J Mol Biol 347:81–93.  https://doi.org/10.1016/j.jmb.2004.12.057 CrossRefPubMedGoogle Scholar
  33. Lithgow T, Junne T, Suda K, Gratzer S, Schatz G (1994) The mitochondrial outer membrane protein Mas22p is essential for protein import and viability of yeast. Proc Natl Acad Sci U S A 91:11973–11977CrossRefPubMedPubMedCentralGoogle Scholar
  34. McKenna NJ, Lanz RB, O’Malley BW (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20:321–344.  https://doi.org/10.1210/edrv.20.3.0366 PubMedGoogle Scholar
  35. Meyer-Almes FJ (2016) Discrimination between conformational selection and induced fit protein-ligand binding using integrated global fit analysis. Eur Biophys J 45:245–257.  https://doi.org/10.1007/s00249-015-1090-1 CrossRefPubMedGoogle Scholar
  36. Michael WM (2000) Nucleocytoplasmic shuttling signals: two for the price of one. Trends Cell Biol 10:46–50CrossRefPubMedGoogle Scholar
  37. Michel D (2016) Conformational selection or induced fit? New insights from old principles. Biochimie 128-129:48–54.  https://doi.org/10.1016/j.biochi.2016.06.012 CrossRefPubMedGoogle Scholar
  38. Mittag T, Kay LE, Forman-Kay JD (2010) Protein dynamics and conformational disorder in molecular recognition. J Mol Recognit 23:105–116.  https://doi.org/10.1002/jmr.961 PubMedGoogle Scholar
  39. Murcha MW, Wang Y, Narsai R, Whelan J (2014) The plant mitochondrial protein import apparatus - the differences make it interesting. Biochim Biophys Acta 1840:1233–1245.  https://doi.org/10.1016/j.bbagen.2013.09.026 CrossRefPubMedGoogle Scholar
  40. Muto T, Obita T, Abe Y, Shodai T, Endo T, Kohda D (2001) NMR identification of the Tom20 binding segment in mitochondrial presequences. J Mol Biol 306:137–143.  https://doi.org/10.1006/jmbi.2000.4397 CrossRefPubMedGoogle Scholar
  41. Nolte RT et al (1998) Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 395:137–143.  https://doi.org/10.1038/25931 CrossRefPubMedGoogle Scholar
  42. Obita T, Muto T, Endo T, Kohda D (2003) Peptide library approach with a disulfide tether to refine the Tom20 recognition motif in mitochondrial presequences. J Mol Biol 328:495–504CrossRefPubMedGoogle Scholar
  43. Okazaki K, Takada S (2008) Dynamic energy landscape view of coupled binding and protein conformational change: induced-fit versus population-shift mechanisms. Proc Natl Acad Sci U S A 105:11182–11187.  https://doi.org/10.1073/pnas.0802524105 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Pandey KN (2010) Small peptide recognition sequence for intracellular sorting. Curr Opin Biotechnol 21:611–620.  https://doi.org/10.1016/j.copbio.2010.08.007 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Paul F, Weikl TR (2016) How to distinguish conformational selection and induced fit based on chemical relaxation rates. PLoS Comput Biol 12:e1005067.  https://doi.org/10.1371/journal.pcbi.1005067 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Perry AJ, Hulett JM, Likic VA, Lithgow T, Gooley PR (2006) Convergent evolution of receptors for protein import into mitochondria. Curr Biol 16:221–229.  https://doi.org/10.1016/j.cub.2005.12.034 CrossRefPubMedGoogle Scholar
  47. Perry AJ, Rimmer KA, Mertens HD, Waller RF, Mulhern TD, Lithgow T, Gooley PR (2008) Structure, topology and function of the translocase of the outer membrane of mitochondria. Plant Physiol Biochem 46:265–274.  https://doi.org/10.1016/j.plaphy.2007.12.012 CrossRefPubMedGoogle Scholar
  48. Plevin MJ, Mills MM, Ikura M (2005) The LxxLL motif: a multifunctional binding sequence in transcriptional regulation. Trends Biochem Sci 30:66–69.  https://doi.org/10.1016/j.tibs.2004.12.001 CrossRefPubMedGoogle Scholar
  49. Rapoport TA, Li L, Park E (2017) Structural and mechanistic insights into protein translocation. Annu Rev Cell Dev Biol 33:369–390.  https://doi.org/10.1146/annurev-cellbio-100616-060439 CrossRefPubMedGoogle Scholar
  50. Rimmer KA et al (2011) Recognition of mitochondrial targeting sequences by the import receptors Tom20 and Tom22. J Mol Biol 405:804–818.  https://doi.org/10.1016/j.jmb.2010.11.017 CrossRefPubMedGoogle Scholar
  51. Saitoh T, Igura M, Miyazaki Y, Ose T, Maita N, Kohda D (2011) Crystallographic snapshots of Tom20-mitochondrial presequence interactions with disulfide-stabilized peptides. Biochemistry 50:5487–5496.  https://doi.org/10.1021/bi200470x CrossRefPubMedGoogle Scholar
  52. Saitoh T et al (2007) Tom20 recognizes mitochondrial presequences through dynamic equilibrium among multiple bound states. EMBO J 26:4777–4787.  https://doi.org/10.1038/sj.emboj.7601888 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Savkur RS, Burris TP (2004) The coactivator LXXLL nuclear receptor recognition motif. J Pept Res 63:207–212.  https://doi.org/10.1111/j.1399-3011.2004.00126.x CrossRefPubMedGoogle Scholar
  54. Shan SO, Walter P (2005) Co-translational protein targeting by the signal recognition particle. FEBS Lett 579:921–926.  https://doi.org/10.1016/j.febslet.2004.11.049 CrossRefPubMedGoogle Scholar
  55. Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (1998) The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95:927–937CrossRefPubMedGoogle Scholar
  56. Vogt AD, Di Cera E (2012) Conformational selection or induced fit? A critical appraisal of the kinetic mechanism. Biochemistry 51:5894–5902.  https://doi.org/10.1021/bi3006913 CrossRefPubMedPubMedCentralGoogle Scholar
  57. von Heijne G (1985) Signal sequences. The limits of variation. J Mol Biol 184:99–105CrossRefGoogle Scholar
  58. von Heijne G (1986) Mitochondrial targeting sequences may form amphiphilic helices. EMBO J 5:1335–1342Google Scholar
  59. Voorhees RM, Hegde RS (2015) Structures of the scanning and engaged states of the mammalian SRP–ribosome complex. Elife 4.  https://doi.org/10.7554/eLife.07975
  60. Walensky LD et al (2004) Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305:1466–1470.  https://doi.org/10.1126/science.1099191 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Werhahn W, Niemeyer A, Jansch L, Kruft V, Schmitz UK, Braun H (2001) Purification and characterization of the preprotein translocase of the outer mitochondrial membrane from Arabidopsis. Identification of multiple forms of TOM20. Plant Physiol 125:943–954CrossRefPubMedPubMedCentralGoogle Scholar
  62. Yamamoto H, Itoh N, Kawano S, Yatsukawa Y, Momose T, Makio T, Matsunaga M, Yokota M, Esaki M, Shodai T, Kohda D, Hobbs AE, Jensen RE, Endo T (2011) Dual role of the receptor Tom20 in specificity and efficiency of protein import into mitochondria. Proc Natl Acad Sci U S A 108:91–96.  https://doi.org/10.1073/pnas.1014918108 CrossRefPubMedGoogle Scholar
  63. Yamano K, Yatsukawa Y, Esaki M, Hobbs AE, Jensen RE, Endo T (2008) Tom20 and Tom22 share the common signal recognition pathway in mitochondrial protein import. J Biol Chem 283:3799–3807.  https://doi.org/10.1074/jbc.M708339200 CrossRefPubMedGoogle Scholar

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© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Division of Structural Biology, Medical Institute of BioregulationKyushu UniversityFukuokaJapan

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