Skip to main content
SpringerLink
Log in

Exploring the Roles of Proline in Three-Dimensional Domain Swapping from Structure Analysis and Molecular Dynamics Simulations

  • Published:
The Protein Journal Aims and scope Submit manuscript

Abstract

Three-dimensional (3D) domain swapping is a mechanism to form protein oligomers. It has been proposed that several factors, including proline residues in the hinge region, may affect the occurrence of 3D domain swapping. Although introducing prolines into the hinge region has been found to promote domain swapping for some proteins, the opposite effect has also been observed in several studies. So far, how proline affects 3D domain swapping remains elusive. In this work, based on a large set of 3D domain-swapped structures, we performed a systematic analysis to explore the correlation between the presence of proline in the hinge region and the occurrence of 3D domain swapping. We further analyzed the conformations of proline and pre-proline residues to investigate the roles of proline in 3D domain swapping. We found that more than 40% of the domain-swapped structures contained proline residues in the hinge region. Unexpectedly, conformational transitions of proline residues were rarely observed upon domain swapping. Our analyses showed that hinge regions containing proline residues preferred more extended conformations, which may be beneficial for the occurrence of domain swapping by facilitating opening of the exchanged segments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Liu YS, Eisenberg D (2002) 3D domain swapping: as domains continue to swap. Protein Sci 11:1285–1299

    Article  CAS  Google Scholar 

  2. Carey J, Lindman S, Bauer M, Linse S (2007) Protein reconstitution and three-dimensional domain swapping: benefits and constraints of covalency. Protein Sci 16:2317–2333

    Article  CAS  Google Scholar 

  3. Gronenborn AM (2009) Protein acrobatics in pairs–dimerization via domain swapping. Curr Opin Struct Biol 19:39–49

    Article  CAS  Google Scholar 

  4. Rousseau F, Schymkowitz J, Itzhaki LS (2012) Implications of 3D domain swapping for protein folding, misfolding and function. Adv Exp Med Biol 747:137–152

    Article  CAS  Google Scholar 

  5. Huang Y, Cao H, Liu Z (2012) Three-dimensional domain swapping in the protein structure space. Proteins 80:1610–1619

    Article  CAS  Google Scholar 

  6. Upadhyay AK, Sowdhamini R (2016) Genome-wide prediction and analysis of 3D-domain swapped proteins in the human genome from sequence information. PLoS ONE 11:e0159627

    Article  Google Scholar 

  7. Mascarenhas NM, Gosavi S (2017) Understanding protein domain-swapping using structure-based models of protein folding. Prog Biophys Mol Biol 128:113–120

    Article  CAS  Google Scholar 

  8. Song G, Jernigan RL (2006) An enhanced elastic network model to represent the motions of domain-swapped proteins. Proteins 63:197–209

    Article  CAS  Google Scholar 

  9. Ding F, Prutzman KC, Campbell SL, Dokholyan NV (2006) Topological determinants of protein domain swapping. Structure 14:5–14

    Article  Google Scholar 

  10. Chu CH, Lo WC, Wang HW, Hsu YC, Hwang JK, Lyu PC, Pai TW, Tang CY (2010) Detection and alignment of 3D domain swapping proteins using angle-distance image-based secondary structural matching techniques. PLoS ONE 5:e13361

    Article  Google Scholar 

  11. Shameer K, Pugalenthi G, Kandaswamy KK, Suganthan PN, Archunan G, Sowdhamini R (2010) Insights into protein sequence and structure-derived features mediating 3D domain swapping mechanism using support vector machine based approach. Bioinform Biol Insights 4:33–42

    Article  CAS  Google Scholar 

  12. Shameer K, Pugalenthi G, Kandaswamy KK, Sowdhamini R (2011) 3dswap-pred: prediction of 3D domain swapping from protein sequence using random forest approach. Protein Pept Lett 18:1010–1020

    Article  CAS  Google Scholar 

  13. Shingate P, Sowdhamini R (2012) Analysis of domain-swapped oligomers reveals local sequence preferences and structural imprints at the linker regions and swapped interfaces. PLoS ONE 7:e39305

    Article  CAS  Google Scholar 

  14. Mazzarella L, Vitagliano L, Zagari A (1995) Swapping structural determinants of ribonucleases: an energetic analysis of the hinge peptide 16–22. Proc Natl Acad Sci USA 92:3799–3803

    Article  CAS  Google Scholar 

  15. Schymkowitz JWH, Rousseau F, Itzhaki LS (2000) Sequence conservation provides the best prediction of the role of proline residues in p13suc1. J Mol Biol 301:199–204

    Article  CAS  Google Scholar 

  16. Kuhlman B, O’Neill JW, Kim DE, Zhang KYJ, Baker D (2001) Conversion of monomeric protein L to an obligate dimer by computational protein design. Proc Natl Acad Sci USA 98:10687–10691

    Article  CAS  Google Scholar 

  17. O’Neill JW, Kim DE, Johnsen K, Baker D, Zhang KYJ (2001) Single-site mutations induce 3D domain swapping in the B1 domain of protein L from Peptostreptococcus magnus. Structure 9:1017–1027

    Article  Google Scholar 

  18. Rousseau F, Schymkowitz JWH, Wilkinson HR, Itzhaki LS (2001) Three-dimensional domain swapping in p13suc1 occurs in the unfolded state and is controlled by conserved proline residues. Proc Natl Acad Sci USA 98:5596–5601

    Article  CAS  Google Scholar 

  19. Woodard JC, Dunatunga S, Shakhnovich EI (2016) A simple model of protein domain swapping in crowded cellular environments. Biophys J 110:2367–2376

    Article  CAS  Google Scholar 

  20. Dehouck Y, Biot C, Gilis D, Kwasigroch JM, Rooman M (2003) Sequence-structure signals of 3D domain swapping in proteins. J Mol Biol 330:1215–1225

    Article  CAS  Google Scholar 

  21. Ogihara NL, Ghirlanda G, Bryson JW, Gingery M, DeGrado WF, Eisenberg D (2001) Design of three-dimensional domain-swapped dimers and fibrous oligomers. Proc Natl Acad Sci USA 98:1404–1409

    Article  CAS  Google Scholar 

  22. Chen YW, Stott K, Perutz MF (1999) Crystal structure of a dimeric chymotrypsin inhibitor 2 mutant containing an inserted glutamine repeat. Proc Natl Acad Sci USA 96:1257–1261

    Article  CAS  Google Scholar 

  23. Tempel W, Liu ZJ, Schubot FD, Shah A, Weinberg MV, Jenney FE, Arendall WB, Adams MWW, Richardson JS, Richardson DC, Rose JP, Wang BC (2004) Structural genomics of Pyrococcus furiosus: X-ray crystallography reveals 3D domain swapping in rubrerythrin. Proteins 57:878–882

    Article  CAS  Google Scholar 

  24. Ha JH, Karchin JM, Walker-Kopp N, Huang LS, Berry EA, Loh SN (2012) Engineering domain-swapped binding interfaces by mutually exclusive folding. J Mol Biol 416:495–502

    Article  CAS  Google Scholar 

  25. Yang SC, Cho SS, Levy Y, Cheung MS, Levine H, Wolynes PG, Onuchic JN (2004) Domain swapping is a consequence of minimal frustration. Proc Natl Acad Sci USA 101:13786–13791

    Article  CAS  Google Scholar 

  26. Kundu S, Jernigan RL (2004) Molecular mechanism of domain swapping in proteins: an analysis of slower motions. Biophys J 86:3846–3854

    Article  CAS  Google Scholar 

  27. Mascarenhas NM, Gosavi S (2016) Protein domain-swapping can be a consequence of functional residues. J Phys Chem B 120:6929–6938

    Article  CAS  Google Scholar 

  28. Rousseau F, Schymkowitz JWH, Itzhaki LS (2003) The unfolding story of three-dimensional domain swapping. Structure 11:243–251

    Article  CAS  Google Scholar 

  29. Liu Z, Huang Y (2013) Evidences for the unfolding mechanism of three-dimensional domain swapping. Protein Sci 22:280–286

    Article  CAS  Google Scholar 

  30. MacArthur MW, Thornton JM (1991) Influence of proline residues on protein conformation. J Mol Biol 218:397–412

    Article  CAS  Google Scholar 

  31. Bergdoll M, Remy MH, Cagnon C, Masson JM, Dumas P (1997) Proline-dependent oligomerization with arm exchange. Structure 5:391–401

    Article  CAS  Google Scholar 

  32. Di Donato A, Cafaro V, D’Alessio G (1994) Ribonuclease A can be transformed into a dimeric ribonuclease with antitumor activity. J Biol Chem 269:17394–17396

    Google Scholar 

  33. Han Z, Xiong C, Mori T, Boyd MR (2002) Discovery of a stable dimeric mutant of cyanovirin-N (CV-N) from a T7 phage-displayed CV-N mutant library. Biochem Biophys Res Commun 292:1036–1043

    Article  CAS  Google Scholar 

  34. Simeoni F, Masotti L, Neyroz P (2001) Structural role of the proline residues of the beta-hinge region of p13suc1 as revealed by site-directed mutagenesis and fluorescence studies. Biochemistry 40:8030–8042

    Article  CAS  Google Scholar 

  35. Barrientos LG, Louis JM, Botos I, Mori T, Han Z, O’Keefe BR, Boyd MR, Wlodawer A, Gronenborn AM (2002) The domain-swapped dimer of cyanovirin-N is in a metastable folded state: reconciliation of X-ray and NMR structures. Structure 10:673–686

    Article  CAS  Google Scholar 

  36. Hakansson M, Svensson A, Fast J, Linse S (2001) An extended hydrophobic core induces EF-hand swapping. Protein Sci 10:927–933

    Article  CAS  Google Scholar 

  37. Miller KH, Karr JR, Marqusee S (2010) A hinge region cis-proline in ribonuclease A acts as a conformational gatekeeper for C-terminal domain swapping. J Mol Biol 400:567–578

    Article  CAS  Google Scholar 

  38. Smaldone G, Vigorita M, Ruggiero A, Balasco N, Dattelbaum JD, D’Auria S, Del Vecchio P, Graziano G, Vitagliano L (2016) Proline 235 plays a key role in the regulation of the oligomeric states of thermotoga maritima arginine binding protein. Biochim Biophys Acta 1864:814–824

    Article  CAS  Google Scholar 

  39. Teplyakov A, Obmolova G, Malia TJ, Luo J, Jacobs SA, Chan W, Domingo D, Baker A, O’Neil KT, Gilliland GL (2014) C-terminal beta-strand swapping in a consensus-derived fibronectin type III scaffold. Proteins 82:1359–1369

    Article  CAS  Google Scholar 

  40. Fox NK, Brenner SE, Chandonia JM (2014) SCOPe: Structural classification of proteins–extended, integrating SCOP and ASTRAL data and classification of new structures. Nucleic Acids Res 42:D304-309

    Article  Google Scholar 

  41. Chandonia JM, Fox NK, Brenner SE (2017) SCOPe: manual curation and artifact removal in the structural classification of proteins—extended database. J Mol Biol 429:348–355

    Article  CAS  Google Scholar 

  42. Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4:435–447

    Article  CAS  Google Scholar 

  43. Berendsen HJC, van der Spoel D, van Drunen R (1995) GROMACS: a message-passing parallel molecular dynamics implementation. Comp Phys Comm 91:43–56

    Article  CAS  Google Scholar 

  44. Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, Dror RO, Shaw DE (2010) Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins 78:1950–1958

    CAS  Google Scholar 

  45. Bourne Y, Arvai AS, Bernstein SL, Watson MH, Reed SI, Endicott JE, Noble ME, Johnson LN, Tainer JA (1995) Crystal structure of the cell cycle-regulatory protein suc1 reveals a beta-hinge conformational switch. Proc Natl Acad Sci USA 92:10232–10236

    Article  CAS  Google Scholar 

  46. Liu YS, Hart PJ, Schlunegger MP, Eisenberg D (1998) The crystal structure of a 3D domain-swapped dimer of RNase A at a 2.1-Å resolution. Proc Natl Acad Sci USA 95:3437–3442

    Article  CAS  Google Scholar 

  47. Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18:2714–2723

    Article  CAS  Google Scholar 

  48. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935

    Article  CAS  Google Scholar 

  49. Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity rescaling. J Chem Phys 126:014101

    Article  Google Scholar 

  50. Parrinello M, Rahman A (1981) Polymorphic transitions in single crystals: a new molecular dynamics method. J Appl Phys 52:7182–7190

    Article  CAS  Google Scholar 

  51. Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092

    Article  CAS  Google Scholar 

  52. Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1997) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18:1463–1472

    Article  CAS  Google Scholar 

  53. Ho BK, Brasseur R (2005) The Ramachandran plots of glycine and pre-proline. BMC Struct Biol 5:14

    Article  Google Scholar 

  54. Newcomer ME (2002) Protein folding and three-dimensional domain swapping: a strained relationship? Curr Opin Struct Biol 12:48–53

    Article  CAS  Google Scholar 

  55. Rodziewicz-Motowidlo S, Iwaszkiewicz J, Sosnowska R, Czaplewska P, Sobolewski E, Szymanska A, Stachowiak K, Liwo A (2009) The role of the Val57 amino-acid residue in the hinge loop of the human cystatin C. Conformational studies of the beta2-L1-beta3 segments of wild-type human cystatin C and its mutants. Biopolymers 91:373–383

    Article  CAS  Google Scholar 

  56. Jenko Kokalj S, Guncar G, Stern I, Morgan G, Rabzelj S, Kenig M, Staniforth RA, Waltho JP, Zerovnik E, Turk D (2007) Essential role of proline isomerization in stefin B tetramer formation. J Mol Biol 366:1569–1579

    Article  CAS  Google Scholar 

  57. Rousseau F, Schymkowitz JW, Sanchez del Pino M, Itzhaki LS (1998) Stability and folding of the cell cycle regulatory protein, p13(suc1). J Mol Biol 284:503–519

    Article  CAS  Google Scholar 

  58. Rousseau F, Schymkowitz JW, Wilkinson HR, Itzhaki LS (2002) The structure of the transition state for folding of domain-swapped dimeric p13suc1. Structure 10:649–657

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No: 21603121, Yongqi Huang) and funding from Hubei University of Technology (Yongqi Huang, Meng Gao, and Zhengding Su).

Author information

Authors and Affiliations

  1. Institute of Biomedical and Pharmaceutical Sciences, Hubei University of Technology, Wuhan, 430068, China

    Yongqi Huang, Meng Gao & Zhengding Su

  2. Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China

    Yongqi Huang, Meng Gao & Zhengding Su

  3. Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China

    Yongqi Huang, Meng Gao & Zhengding Su

  4. Hubei Collaborative Innovation Center for Industrial Fermentation, Hubei University of Technology, Wuhan, China

    Yongqi Huang, Meng Gao & Zhengding Su

Authors
  1. Yongqi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhengding Su
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yongqi Huang or Zhengding Su.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, Y., Gao, M. & Su, Z. Exploring the Roles of Proline in Three-Dimensional Domain Swapping from Structure Analysis and Molecular Dynamics Simulations. Protein J 37, 13–20 (2018). https://doi.org/10.1007/s10930-017-9747-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10930-017-9747-5

Keywords

Search

Navigation