κ-helix and the helical lock and key model: a pivotal way of looking at polyproline II

MOTIVATION Polyproline II (PPII) is a common conformation, comparable to α-helix and β-sheet and is a candidate for being the most prevalent secondary structure. PPII, recently termed with a more generic name - κ-helix, adopts a left-handed structure with 3-fold rotational symmetry. Lately, a new type of binding mechanism - the helical lock and key model was introduced in SH3-domain complexes, where the interaction is characterized by a sliding helical pattern. However, whether this binding mechanism is unique only to SH3 domains is unreported. RESULTS Here, we show that the helical binding pattern is a universal feature of the κ-helix conformation, present within all the major target families - SH3, WW, profilin, MHC-II, EVH1, and GYF domains. Based on a geometric analysis of 255 experimentally solved structures, we found that they are characterized by a distinctive rotational angle along the helical axis. Furthermore, we found that the range of helical pitch varies between different protein domains or peptide orientations and that the interaction is also represented by a rotational displacement mimicking helical motion. The discovery of rotational interactions as a mechanism, reveals a new dimension in the realm of protein-protein interactions, which introduces a new layer of information encoded by the helical conformation. Due to the extensive involvement of the conformation in functional interactions, we anticipate our model to expand the current molecular understanding of the relationship between protein structure and function. AVAILABILITY We have implemented the proposed methods in an R package freely available at https://github.com/Grantlab/bio3d. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

[1]  V. Tumanyan,et al.  Omnipresence of the polyproline II helix in fibrous and globular proteins. , 2017, Current opinion in structural biology.

[2]  M. Sternberg,et al.  Left-handed polyproline II helices commonly occur in globular proteins. , 1993, Journal of molecular biology.

[3]  Abraham O. Samson,et al.  A helical lock and key model of polyproline II conformation with SH3 , 2019, Bioinform..

[4]  V. Pande,et al.  Unusual compactness of a polyproline type II structure. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  T. Creamer,et al.  A survey of left‐handed polyproline II helices , 2008, Protein science : a publication of the Protein Society.

[6]  M. Sternberg,et al.  Polyproline-II helix in proteins: structure and function. , 2013, Journal of molecular biology.

[7]  R. Germain,et al.  Antigen presentation by MHC class II molecules: invariant chain function, protein trafficking, and the molecular basis of diverse determinant capture. , 1997, Human immunology.

[8]  E. Milner-White,et al.  Predicting the conformations of peptides and proteins in early evolution. A review article submitted to Biology Direct , 2008, Biology Direct.

[9]  V. Hsu,et al.  The extended left‐handed helix: A simple nucleic acid‐binding motif , 2004, Proteins.

[10]  Ronald Kühne,et al.  Recognition of proline-rich motifs by protein-protein-interaction domains. , 2005, Angewandte Chemie.

[11]  Leo S. D. Caves,et al.  Bio3d: An R Package , 2022 .

[12]  Abhishek K. Jha,et al.  Helix, sheet, and polyproline II frequencies and strong nearest neighbor effects in a restricted coil library. , 2005, Biochemistry.

[13]  M. Sternberg,et al.  Conservation of polyproline II helices in homologous proteins: Implications for structure prediction by model building , 1994, Protein science : a publication of the Protein Society.

[14]  T. Creamer,et al.  Determinants of the polyproline II helix from modeling studies. , 2002, Advances in protein chemistry.

[15]  P Andrew Karplus,et al.  On the occurrence of linear groups in proteins , 2009, Protein science : a publication of the Protein Society.

[16]  Frederick Grinnell,et al.  Fibroblast mechanics in 3D collagen matrices. , 2007, Advanced drug delivery reviews.

[17]  M G Fried,et al.  Host-guest study of left-handed polyproline II helix formation. , 2001, Biochemistry.

[18]  H. Rosu.  On the kinks and dynamical phase transitions of α-helix protein chains , 1995, cond-mat/9510019.

[19]  David Eisenberg,et al.  The discovery of the α-helix and β-sheet, the principal structural features of proteins , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[20]  A. Drake,et al.  The importance of extended conformations and, in particular, the PII conformation for the molecular recognition of peptides , 1995, Biopolymers.

[21]  Martti Juhola,et al.  On preprocessing of protein sequences for neural network prediction of polyproline type II secondary structures , 2001, Comput. Biol. Medicine.

[22]  T L Blundell,et al.  Properties of polyproline II, a secondary structure element implicated in protein–protein interactions , 2005, Proteins.

[23]  M. DePristo,et al.  Simultaneous determination of protein structure and dynamics , 2005, Nature.

[24]  E. Gazit,et al.  The Self‐Assembly of Helical Peptide Building Blocks , 2016 .

[25]  Engelbert Buxbaum,et al.  Fundamentals of Protein Structure and Function , 2015, Springer International Publishing.

[26]  M. Billeter.  A consensus on protein structure accuracy in NMR? , 2015, Structure.

[27]  Tomonori Kaneko,et al.  The SH3 domain--a family of versatile peptide- and protein-recognition module. , 2008, Frontiers in bioscience : a journal and virtual library.

[28]  A. Zewail,et al.  Primary peptide folding dynamics observed with ultrafast temperature jump. , 2009, Angewandte Chemie.

[29]  R. Hodges,et al.  De novo design of α-helical coiled coils and bundles: models for the development of protein-design principles , 1998 .

[30]  A. D. de Brevern,et al.  Assignment of PolyProline II Conformation and Analysis of Sequence – Structure Relationship , 2011, PloS one.

[31]  B. Matthews,et al.  Structural basis of amino acid alpha helix propensity. , 1993, Science.

[32]  Robyn L Stanfield,et al.  How TCRs bind MHCs, peptides, and coreceptors. , 2006, Annual review of immunology.

[33]  Wenbo Xu,et al.  Prediction by support vector machines and analysis by Z-score of poly-l-proline type II conformation based on local sequence , 2005, Comput. Biol. Chem..

[34]  R. Berisio,et al.  Polyproline helices in protein structures: A statistical survey. , 2006, Protein and peptide letters.

[35]  A Caflisch,et al.  Slow folding of cross-linked alpha-helical peptides due to steric hindrance. , 2010, The journal of physical chemistry. B.

[36]  B. Callewaert,et al.  The Genetics of Soft Connective Tissue Disorders. , 2015, Annual review of genomics and human genetics.

[37]  Jean Martínez,et al.  Silaproline helical mimetics selectively form an all-trans PPII helix. , 2014, Chemistry.

[38]  M. Sela,et al.  Studies on the structure of poly-L-proline in solution. , 1958, Biochimica et biophysica acta.

[39]  M R Holt,et al.  Cell motility: proline-rich proteins promote protrusions. , 2001, Trends in cell biology.

[40]  Zhongyan Li,et al.  Is protein context responsible for peptide-mediated interactions? , 2019, Molecular omics.

[41]  L. Barron,et al.  Ramachandran mapping of peptide conformation using a large database of computed Raman and Raman optical activity spectra. , 2016, Physical chemistry chemical physics : PCCP.

[42]  J. Baum,et al.  Conformational characterization of a helix-nucleated bicyclic GCN4 decapeptide by proton NMR. , 2000, The journal of peptide research : official journal of the American Peptide Society.

[43]  V. Agrawal,et al.  Promiscuous binding nature of SH3 domains to their target proteins. , 2002, Protein and peptide letters.

[44]  J. Greenbaum,et al.  Improved methods for predicting peptide binding affinity to MHC class II molecules , 2018, Immunology.

[45]  Brian F. Fisher,et al.  Thermodynamic Scale of β-Amino Acid Residue Propensities for an α-Helix-like Conformation. , 2018, Journal of the American Chemical Society.