Amino Acids

, Volume 49, Issue 4, pp 705–713 | Cite as

Recent advances on polyproline II

  • Tarun Jairaj Narwani
  • Hubert Santuz
  • Nicolas Shinada
  • Akhila Melarkode Vattekatte
  • Yassine Ghouzam
  • Narayanasamy Srinivasan
  • Jean-Christophe GellyEmail author
  • Alexandre G. de BrevernEmail author
Minireview Article


About half of the globular proteins are composed of regular secondary structures, α-helices, and β-sheets, while the rest are constituted of irregular secondary structures, such as turns or coil conformations. Other regular secondary structures are often ignored, despite their importance in biological processes. Among such structures, the polyproline II helix (PPII) has interesting behaviours. PPIIs are not usually associated with conventional stabilizing interactions, and recent studies have observed that PPIIs are more frequent than anticipated. In addition, it is suggested that they may have an important functional role, particularly in protein–protein or protein–nucleic acid interactions and recognition. Residues associated with PPII conformations represent nearly 5% of the total residues, but the lack of PPII assignment approaches prevents their systematic analysis. This short review will present current knowledge and recent research in PPII area. In a first step, the different methodologies able to assign PPII are presented. In the second step, recent studies that have shown new perspectives in PPII analysis in terms of structure and function are underlined with three cases: (1) PPII in protein structures. For instance, the first crystal structure of an oligoproline adopting an all-trans polyproline II (PPII) helix had been presented; (2) the involvement of PPII in different diseases and drug designs; and (3) an interesting extension of PPII study in the protein dynamics. For instance, PPIIs are often linked to disorder region analysis and the precise analysis of a potential PPII helix in hypogonadism shows unanticipated PPII formations in the patient mutation, while it is not observed in the wild-type form of KISSR1 protein.


Secondary structure Sequence structure relationship Structural alphabet Local protein conformations Frameworks 



We would like to thank Catherine Etchebest for fruitful discussions. This work was supported by grants from the Ministry of Research (France), University Paris Diderot, Sorbonne, Paris Cité (France), National Institute for Blood Transfusion (INTS, France), National Institute for Health and Medical Research (INSERM, France), and labex GR-Ex. The labex GR-Ex, reference ANR-11-LABX-0051 is funded by the program “Investissements d’avenir” of the French National Research Agency, reference ANR-11-IDEX-0005-02. TjrN, NSr, and AdB acknowledge to Indo-French Centre for the Promotion of Advanced Research/CEFIPRA for collaborative grant (number 5302-2). NSh acknowledges support from ANRT (CIFRE convention number 2015/0832). NSr acknowledges for J.C. Bose fellowship and general support from DBT. AMV is supported by Allocations Regionales de Researche grant from Region Reunion.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Adzhubei AA, Sternberg MJ (1993) Left-handed polyproline II helices commonly occur in globular proteins. J Mol Biol 229:472–493. doi: 10.1006/jmbi.1993.1047 CrossRefPubMedGoogle Scholar
  2. Adzhubei AA, Sternberg MJ, Makarov AA (2013) Polyproline-II helix in proteins: structure and function. J Mol Biol 425:2100–2132. doi: 10.1016/j.jmb.2013.03.018 CrossRefPubMedGoogle Scholar
  3. Adzhubei AA, Anashkina AA, Makarov AA (2016) Left-handed polyproline-II helix revisited: proteins causing proteopathies. J Biomol Struct Dyn. doi: 10.1080/07391102.2016.1229220 PubMedGoogle Scholar
  4. Agrawal V, Kishan KV (2002) Promiscuous binding nature of SH3 domains to their target proteins. Protein Pept Lett 9:185–193CrossRefPubMedGoogle Scholar
  5. Aksianov E, Alexeevski A (2012) SheeP: a tool for description of beta-sheets in protein 3D structures. J Bioinform Comput Biol 10:1241003. doi: 10.1142/S021972001241003X CrossRefPubMedGoogle Scholar
  6. Arnott S, Dover SD (1968) The structure of poly-l-proline II. Acta Crystallogr B 24:599–601CrossRefPubMedGoogle Scholar
  7. Bansal M, Kumar S, Velavan R (2000) HELANAL: a program to characterize helix geometry in proteins. J Biomol Struct Dyn 17:811–819. doi: 10.1080/07391102.2000.10506570 CrossRefPubMedGoogle Scholar
  8. Bella J, Eaton M, Brodsky B, Berman HM (1994) Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution. Science 266:75–81CrossRefPubMedGoogle Scholar
  9. Berman HM et al (2000) The Protein Data Bank. Nucleic Acids Res 28:235–242CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bernstein FC et al (1977) The protein data bank: a computer-based archival file for macromolecular structures. J Mol Biol 112:535–542CrossRefPubMedGoogle Scholar
  11. Blanch EW, Morozova-Roche LA, Cochran DA, Doig AJ, Hecht L, Barron LD (2000) Is polyproline II helix the killer conformation? A Raman optical activity study of the amyloidogenic prefibrillar intermediate of human lysozyme. J Mol Biol 301:553–563. doi: 10.1006/jmbi.2000.3981 CrossRefPubMedGoogle Scholar
  12. Bochicchio B, Tamburro AM (2002) Polyproline II structure in proteins: identification by chiroptical spectroscopies, stability, and functions. Chirality 14:782–792. doi: 10.1002/chir.10153 CrossRefPubMedGoogle Scholar
  13. Booker GW, Breeze AL, Downing AK, Panayotou G, Gout I, Waterfield MD, Campbell ID (1992) Structure of an SH2 domain of the p85 alpha subunit of phosphatidylinositol-3-OH kinase. Nature 358:684–687. doi: 10.1038/358684a0 CrossRefPubMedGoogle Scholar
  14. Bornot A, de Brevern AG (2006) Protein beta-turn assignments. Bioinformation 1:153–155CrossRefPubMedPubMedCentralGoogle Scholar
  15. Cao C, Wang G, Liu A, Xu S, Wang L, Zou S (2016) A new secondary structure assignment algorithm using calpha backbone fragments. Int J Mol Sci 17:333. doi: 10.3390/ijms17030333 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Carter P, Andersen CA, Rost B (2003) DSSPcont: continuous secondary structure assignments for proteins. Nucleic Acids Res 31:3293–3295CrossRefPubMedPubMedCentralGoogle Scholar
  17. Carugo O, Djinovic-Carugo K (2013) Half a century of Ramachandran plots. Acta Crystallogr D Biol Crystallogr 69:1333–1341. doi: 10.1107/S090744491301158X CrossRefPubMedGoogle Scholar
  18. Chebrek R, Leonard S, de Brevern AG, Gelly JC (2014) PolyprOnline: polyproline helix II and secondary structure assignment database Database (Oxford) 2014 doi: 10.1093/database/bau102
  19. Chevrier L, de Brevern A, Hernandez E, Leprince J, Vaudry H, Guedj AM, de Roux N (2013) PRR repeats in the intracellular domain of KISS1R are important for its export to cell membrane. Mol Endocrinol 27:1004–1014. doi: 10.1210/me.2012-1386 CrossRefPubMedGoogle Scholar
  20. Cowan PM, McGavin S, North AC (1955) The polypeptide chain configuration of collagen. Nature 176:1062–1064CrossRefPubMedGoogle Scholar
  21. Creamer TP (1998) Left-handed polyproline II helix formation is (very) locally driven. Proteins 33:218–226CrossRefPubMedGoogle Scholar
  22. Cubellis MV, Caillez F, Blundell TL, Lovell SC (2005a) Properties of polyproline II, a secondary structure element implicated in protein-protein interactions. Proteins 58:880–892. doi: 10.1002/prot.20327 CrossRefPubMedGoogle Scholar
  23. Cubellis MV, Cailliez F, Lovell SC (2005b) Secondary structure assignment that accurately reflects physical and evolutionary characteristics. BMC Bioinform 6(Suppl 4):S8. doi: 10.1186/1471-2105-6-S4-S8 CrossRefGoogle Scholar
  24. Delano WL (2013) The PyMOL molecular graphics system on World Wide Web. Accessed 3 Jan 2017
  25. Dupuis F, Sadoc JF, Mornon JP (2004) Protein secondary structure assignment through Voronoi tessellation. Proteins 55:519–528. doi: 10.1002/prot.10566 CrossRefPubMedGoogle Scholar
  26. Eiriksdottir E, Konate K, Langel U, Divita G, Deshayes S (2010) Secondary structure of cell-penetrating peptides controls membrane interaction and insertion. Biochim Biophys Acta 1798:1119–1128. doi: 10.1016/j.bbamem.2010.03.005 CrossRefPubMedGoogle Scholar
  27. Eisenberg D (2003) The discovery of the alpha-helix and beta-sheet, the principal structural features of proteins. Proc Natl Acad Sci USA 100:11207–11210CrossRefPubMedPubMedCentralGoogle Scholar
  28. Ferreon JC, Hilser VJ (2003) The effect of the polyproline II (PPII) conformation on the denatured state entropy. Protein Sci 12:447–457. doi: 10.1110/ps.0237803 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Fillon YA, Anderson JP, Chmielewski J (2005) Cell penetrating agents based on a polyproline helix scaffold. J Am Chem Soc 127:11798–11803. doi: 10.1021/ja052377g CrossRefPubMedGoogle Scholar
  30. Fodje MN, Al-Karadaghi S (2002) Occurrence, conformational features and amino acid propensities for the pi-helix. Protein Eng 15:353–358CrossRefPubMedGoogle Scholar
  31. Foged C, Nielsen HM (2008) Cell-penetrating peptides for drug delivery across membrane barriers. Expert Opin Drug Deliv 5:105–117. doi: 10.1517/17425247.5.1.105 CrossRefPubMedGoogle Scholar
  32. Franz J, Lelle M, Peneva K, Bonn M, Weidner T (2016) SAP(E)—a cell-penetrating polyproline helix at lipid interfaces. Biochim Biophys Acta 1858:2028–2034. doi: 10.1016/j.bbamem.2016.05.021 CrossRefPubMedGoogle Scholar
  33. Frishman D, Argos P (1995) Knowledge-based protein secondary structure assignment. Proteins 23:566–579. doi: 10.1002/prot.340230412 CrossRefPubMedGoogle Scholar
  34. Geisler I, Chmielewski J (2009) Cationic amphiphilic polyproline helices: side-chain variations and cell-specific internalization. Chem Biol Drug Des 73:39–45. doi: 10.1111/j.1747-0285.2008.00759.x CrossRefPubMedGoogle Scholar
  35. Hicks JM, Hsu VL (2004) The extended left-handed helix: a simple nucleic acid-binding motif. Proteins 55:330–338. doi: 10.1002/prot.10630 CrossRefPubMedGoogle Scholar
  36. Hosseini SR, Sadeghi M, Pezeshk H, Eslahchi C, Habibi M (2008) PROSIGN: a method for protein secondary structure assignment based on three-dimensional coordinates of consecutive C(alpha) atoms. Comput Biol Chem 32:406–411. doi: 10.1016/j.compbiolchem.2008.07.027 CrossRefPubMedGoogle Scholar
  37. Hutchinson EG, Thornton JM (1996) PROMOTIF—a program to identify and analyze structural motifs in proteins. Protein Sci 5:212–220. doi: 10.1002/pro.5560050204 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Jha AK, Colubri A, Zaman MH, Koide S, Sosnick TR, Freed KF (2005) Helix, sheet, and polyproline II frequencies and strong nearest neighbor effects in a restricted coil library. Biochemistry 44:9691–9702. doi: 10.1021/bi0474822 CrossRefPubMedGoogle Scholar
  39. Kabsch W, Sander C (1983) Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22:2577–2637. doi: 10.1002/bip.360221211 CrossRefPubMedGoogle Scholar
  40. King SM, Johnson WC (1999) Assigning secondary structure from protein coordinate data. Proteins 35:313–320CrossRefPubMedGoogle Scholar
  41. Kneller GR, Hinsen K (2015) Protein secondary-structure description with a coarse-grained model. Acta Crystallogr D Biol Crystallogr 71:1411–1422. doi: 10.1107/S1399004715007191 CrossRefPubMedGoogle Scholar
  42. Koleske AJ, Buratowski S, Nonet M, Young RA (1992) A novel transcription factor reveals a functional link between the RNA polymerase II CTD and TFIID. Cell 69:883–894CrossRefPubMedGoogle Scholar
  43. Kumar P, Bansal M (2015) Identification of local variations within secondary structures of proteins. Acta Crystallogr D Biol Crystallogr 71:1077–1086. doi: 10.1107/S1399004715003144 CrossRefPubMedGoogle Scholar
  44. Kumar P, Bansal M (2016) Structural and functional analyses of PolyProline-II helices in globular proteins. J Struct Biol 196:414–425. doi: 10.1016/j.jsb.2016.09.006 CrossRefPubMedGoogle Scholar
  45. Labesse G, Colloc’h N, Pothier J, Mornon JP (1997) P-SEA: a new efficient assignment of secondary structure from C alpha trace of proteins. Comput Appl Biosci 13:291–295PubMedGoogle Scholar
  46. Law SM, Frank AT, Brooks CL 3rd (2014) PCASSO: a fast and efficient Calpha-based method for accurately assigning protein secondary structure elements. J Comput Chem 35:1757–1761. doi: 10.1002/jcc.23683 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Lewis HA, Musunuru K, Jensen KB, Edo C, Chen H, Darnell RB, Burley SK (2000) Sequence-specific RNA binding by a Nova KH domain: implications for paraneoplastic disease and the fragile X syndrome. Cell 100:323–332CrossRefPubMedGoogle Scholar
  48. Li L, Geisler I, Chmielewski J, Cheng JX (2010) Cationic amphiphilic polyproline helix P11LRR targets intracellular mitochondria. J Control Release 142:259–266. doi: 10.1016/j.jconrel.2009.10.012 CrossRefPubMedGoogle Scholar
  49. Majumdar I, Krishna SS, Grishin NV (2005) PALSSE: a program to delineate linear secondary structural elements from protein structures. BMC Bioinformatics 6:202. doi: 10.1186/1471-2105-6-202 CrossRefPubMedPubMedCentralGoogle Scholar
  50. Mansiaux Y, Joseph AP, Gelly JC, de Brevern AG (2011) Assignment of polyproline II conformation and analysis of sequence–structure relationship. PLoS One 6:e18401. doi: 10.1371/journal.pone.0018401 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Martin J, Letellier G, Marin A, Taly JF, de Brevern AG, Gibrat JF (2005) Protein secondary structure assignment revisited: a detailed analysis of different assignment methods. BMC Struct Biol 5:17. doi: 10.1186/1472-6807-5-17 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Offmann B, Tyagi M, de Brevern AG (2007) Local protein structures. Curr Bioinform 3:165–202CrossRefGoogle Scholar
  53. Oluwatobi Salawu E (2016) RaFoSA: random forests secondary structure assignment for coarse-grained and all-atom protein systems. Cogent Biol 2:1214061Google Scholar
  54. Parisien M, Major F (2005) A new catalog of protein beta-sheets proteins 61:545–558. doi: 10.1002/prot.20677 PubMedGoogle Scholar
  55. Park SY, Yoo MJ, Shin J, Cho KH (2011) SABA (secondary structure assignment program based on only alpha carbons): a novel pseudo center geometrical criterion for accurate assignment of protein secondary structures. BMB Rep 44:118–122. doi: 10.5483/BMBRep CrossRefPubMedGoogle Scholar
  56. Pauling L, Corey RB (1950) Two hydrogen-bonded spiral configurations of the polypetide chain. J Am Chem Soc 72:5349CrossRefGoogle Scholar
  57. Pauling L, Corey RB (1951a) The pleated sheet, a new layer configuration of polypeptide chains. Proc Natl Acad Sci USA 37:251–256CrossRefPubMedPubMedCentralGoogle Scholar
  58. Pauling L, Corey RB (1951b) The structure of fibrous proteins of the collagen-gelatin group. Proc Natl Acad Sci USA 37:272–281CrossRefPubMedPubMedCentralGoogle Scholar
  59. Pauling L, Corey RB, Branson HR (1951) The structure of proteins; two hydrogen-bonded helical configurations of the polypeptide chain. Proc Natl Acad Sci USA 37:205–211CrossRefPubMedPubMedCentralGoogle Scholar
  60. Pronk S et al (2013) GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29:845–854. doi: 10.1093/bioinformatics/btt055 CrossRefPubMedPubMedCentralGoogle Scholar
  61. R Core Team (2013) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  62. Ramachandran GN, Ramakrishnan C, Sasisekharan V (1963) Stereochemistry of polypeptide chain configurations. J Mol Biol 7:95–99CrossRefPubMedGoogle Scholar
  63. Rich A, Crick FH (1955) The structure of collagen. Nature 176:915–916CrossRefPubMedGoogle Scholar
  64. Richards FM, Kundrot CE (1988) Identification of structural motifs from protein coordinate data: secondary structure and first-level supersecondary structure. Proteins 3:71–84. doi: 10.1002/prot.340030202 CrossRefPubMedGoogle Scholar
  65. Richardson JS (1981) The anatomy and taxonomy of protein structure. Adv Protein Chem 34:167–339CrossRefPubMedGoogle Scholar
  66. Rose GD (1978) Prediction of chain turns in globular proteins on a hydrophobic basis. Nature 272:586–590CrossRefPubMedGoogle Scholar
  67. Ruzza P, Calderan A, Guiotto A, Osler A, Borin G (2004) Tat cell-penetrating peptide has the characteristics of a poly(proline) II helix in aqueous solution and in SDS micelles. J Pept Sci 10:423–426. doi: 10.1002/psc.558 CrossRefPubMedGoogle Scholar
  68. Sasisekharan V (1959) Structure of poly-l-proline II. Acta Crystallogr 12:897–903CrossRefGoogle Scholar
  69. Shakarji CM (1998) Least-squares fitting algorithms of the NIST algorithm testing system. J Res Natl Inst Stand Technol 103:633CrossRefPubMedPubMedCentralGoogle Scholar
  70. Sklenar H, Etchebest C, Lavery R (1989) Describing protein structure: a general algorithm yielding complete helicoidal parameters and a unique overall axis. Proteins 6:46–60. doi: 10.1002/prot.340060105 CrossRefPubMedGoogle Scholar
  71. Soman KV, Ramakrishnan C (1983) Occurrence of a single helix of the collagen type in globular proteins. J Mol Biol 170:1045–1048CrossRefPubMedGoogle Scholar
  72. Sreerama N, Woody RW (1994) Poly(pro)II helices in globular proteins: identification and circular dichroic analysis. Biochemistry 33:10022–10025CrossRefPubMedGoogle Scholar
  73. Sreerama N, Woody RW (2003) Structural composition of betaI- and betaII-proteins. Protein Sci 12:384–388. doi: 10.1110/ps.0235003 CrossRefPubMedPubMedCentralGoogle Scholar
  74. Srinivasan R, Rose GD (1999) A physical basis for protein secondary structure. Proc Natl Acad Sci USA 96:14258–14263CrossRefPubMedPubMedCentralGoogle Scholar
  75. Stapley BJ, Creamer TP (1999) A survey of left-handed polyproline II helices. Protein Sci 8:587–595. doi: 10.1110/ps.8.3.587 CrossRefPubMedPubMedCentralGoogle Scholar
  76. Sugeta H, Miyazawa T (1967) General method for calculating helical parameters of polymer chains from bond lengths, bond angles, and internal-rotation angles. Biopolymers 5:673–679CrossRefGoogle Scholar
  77. Suzuki M (1989) SPXX, a frequent sequence motif in gene regulatory proteins. J Mol Biol 207:61–84CrossRefPubMedGoogle Scholar
  78. Suzuki M, Sohma H, Yazawa M, Yagi K, Ebashi S (1990) Histone H1 kinase specific to the SPKK motif. J Biochem 108:356–364CrossRefPubMedGoogle Scholar
  79. Syme CD, Blanch EW, Holt C, Jakes R, Goedert M, Hecht L, Barron LD (2002) A Raman optical activity study of rheomorphism in caseins, synucleins and tau. New insight into the structure and behaviour of natively unfolded proteins. Eur J Biochem 269:148–156CrossRefPubMedGoogle Scholar
  80. Toal S, Schweitzer-Stenner R (2014) Local order in the unfolded state: conformational biases and nearest neighbor interactions. Biomolecules 4:725–773. doi: 10.3390/biom4030725 CrossRefPubMedPubMedCentralGoogle Scholar
  81. Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718. doi: 10.1002/jcc.20291 CrossRefGoogle Scholar
  82. Venkatachalam CM (1968) Stereochemical criteria for polypeptides and proteins. V. Conformation of a system of three linked peptide units. Biopolymers 6:1425–1436CrossRefPubMedGoogle Scholar
  83. Whittington SJ, Chellgren BW, Hermann VM, Creamer TP (2005) Urea promotes polyproline II helix formation: implications for protein denatured states. Biochemistry 44:6269–6275. doi: 10.1021/bi050124u CrossRefPubMedGoogle Scholar
  84. Williamson MP (1994) The structure and function of proline-rich regions in proteins. Biochem J 297(Pt 2):249–260CrossRefPubMedPubMedCentralGoogle Scholar
  85. Yamashita H et al (2016) Development of a cell-penetrating peptide that exhibits responsive changes in its secondary structure in the cellular environment. Sci Rep 6:33003. doi: 10.1038/srep33003 CrossRefPubMedPubMedCentralGoogle Scholar
  86. Zacharias J, Knapp EW (2014) Protein secondary structure classification revisited: processing DSSP information with PSSC. J Chem Inf Model 54:2166–2179. doi: 10.1021/ci5000856 CrossRefPubMedGoogle Scholar
  87. Zhang Y, Sagui C (2015) Secondary structure assignment for conformationally irregular peptides: comparison between DSSP, STRIDE and KAKSI. J Mol Graph Model 55:72–84. doi: 10.1016/j.jmgm.2014.10.005 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2017

Authors and Affiliations

  • Tarun Jairaj Narwani
    • 1
    • 2
    • 3
    • 4
  • Hubert Santuz
    • 1
    • 2
    • 3
    • 4
  • Nicolas Shinada
    • 1
    • 2
    • 3
    • 4
    • 5
  • Akhila Melarkode Vattekatte
    • 1
    • 2
    • 3
    • 4
    • 6
  • Yassine Ghouzam
    • 1
    • 2
    • 3
    • 4
  • Narayanasamy Srinivasan
    • 7
  • Jean-Christophe Gelly
    • 1
    • 2
    • 3
    • 4
    Email author
  • Alexandre G. de Brevern
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.INSERM, U 1134, DSIMBParis Cedex 15France
  2. 2.Univ Paris Diderot, Sorbonne Paris Cité, UMR_S 1134ParisFrance
  3. 3.Institut National de la Transfusion Sanguine (INTS)ParisFrance
  4. 4.Laboratoire d’Excellence GR-ExParisFrance
  5. 5.Discngine, SASParisFrance
  6. 6.Univ de La Réunion, DSIMB, UMR-S S1134Saint DenisFrance
  7. 7.Molecular Biophysics UnitIndian Institute of ScienceBangaloreIndia

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