A helical lock and key model of polyproline II conformation with SH3

Tomer Meirson, David Bomze, Liron Kahlon, Hava Gil-Henn, Abraham O. Samson

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Motivation: More than half of the human proteome contains the proline-rich motif, PxxP. This motif has a high propensity for adopting a left-handed polyproline II (PPII) helix and can potentially bind SH3 domains. SH3 domains are generally grouped into two classes, based on whether the PPII binds in a positive (N-to-C terminal) or negative (C-to-N terminal) orientation. Since the discovery of this structural motif, over six decades ago, a systematic understanding of its binding remains poor and the consensus amino acid sequence that binds SH3 domains is still ill defined. Results: Here, we show that the PPII interaction with SH3 domains is governed by the helix backbone and its prolines, and their rotation angle around the PPII helical axis. Based on a geometric analysis of 131 experimentally solved SH3 domains in complex with PPIIs, we observed a rotary translation along the helical screw axis, and separated them by 120° into three categories we name α (0-120°), β (120-240°) and γ(240-360°). Furthermore, we found that PPII helices are distinguished by a shifting PxxP motif preceded by positively charged residues which act as a structural reading frame and dictates the organization of SH3 domains; however, there is no one single consensus motif for all classified PPIIs. Our results demonstrate a remarkable apparatus of a lock with a rotating and translating key with no known equivalent machinery in molecular biology. We anticipate our model to be a starting point for deciphering the PPII code, which can unlock an exponential growth in our understanding of the relationship between protein structure and function.

Original languageEnglish
Pages (from-to)154-159
Number of pages6
JournalBioinformatics
Volume36
Issue number1
DOIs
StatePublished - 1 Jan 2020

Bibliographical note

Publisher Copyright:
© 2019 The Author(s) . Published by Oxford University Press. All rights reserved.

Funding

This work was supported by the Leir Foundation and the Ginzburg Foundation (to Abraham O. Samson), and by the Israel Cancer Association and Estee Lauder Companies (grant No. 20180089), the Israel Cancer Research Foundation (grant No. 17-902-AG) and the Israel Science Foundation (grant No. 1462/17) (to Hava Gil-Henn). Tomer Meirson was supported by the Foulkes Foundation fellowship for MD/PhD students.

FundersFunder number
Estee Lauder Companies20180089
Ginzburg Foundation
Israel Cancer Research Fund17-902-AG
Leir Foundation
Foulkes Foundation
Israel Cancer Association
Israel Science Foundation1462/17

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