{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T22:12:57Z","timestamp":1766268777466,"version":"3.37.3"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2019,6,28]],"date-time":"2019-06-28T00:00:00Z","timestamp":1561680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Leir Foundation and the Ginzburg Foundation"},{"name":"Israel Cancer Association and Estee Lauder Companies","award":["20180089"],"award-info":[{"award-number":["20180089"]}]},{"name":"Israel Cancer Research Foundation","award":["17-902-AG"],"award-info":[{"award-number":["17-902-AG"]}]},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["1462\/17"],"award-info":[{"award-number":["1462\/17"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000618","name":"Foulkes Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000618","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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\u00b0 into three categories we name \u03b1 (0\u2013120\u00b0), \u03b2 (120\u2013240\u00b0) and \u03b3 (240\u2013360\u00b0). 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>We have implemented the proposed methods in the R software environment and in an R package freely available at https:\/\/github.com\/Grantlab\/bio3d.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btz527","type":"journal-article","created":{"date-parts":[[2019,6,25]],"date-time":"2019-06-25T18:40:38Z","timestamp":1561488038000},"page":"154-159","source":"Crossref","is-referenced-by-count":12,"title":["A helical lock and key model of polyproline II conformation with SH3"],"prefix":"10.1093","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5011-5477","authenticated-orcid":false,"given":"Tomer","family":"Meirson","sequence":"first","affiliation":[{"name":"Drug Discovery Laboratory, The Azrieli Faculty of Medicine , Safed 1589, Israel"},{"name":"Laboratory of Cell Migration and Invasion, The Azrieli Faculty of Medicine, Bar-Ilan University , Safed 1589, Israel"}]},{"given":"David","family":"Bomze","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 39040, Israel"}]},{"given":"Liron","family":"Kahlon","sequence":"additional","affiliation":[{"name":"The Azrieli Faculty of Medicine, Bar-Ilan University , Safed 1589, Israel"}]},{"given":"Hava","family":"Gil-Henn","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Migration and Invasion, The Azrieli Faculty of Medicine, Bar-Ilan University , Safed 1589, Israel"}]},{"given":"Abraham O","family":"Samson","sequence":"additional","affiliation":[{"name":"Drug Discovery Laboratory, The Azrieli Faculty of Medicine , Safed 1589, Israel"}]}],"member":"286","published-online":{"date-parts":[[2019,6,28]]},"reference":[{"key":"2023013109502411700_btz527-B1","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1006\/jmbi.1993.1047","article-title":"Left-handed polyproline II helices commonly occur in globular proteins","volume":"229","author":"Adzhubei","year":"1993","journal-title":"J. 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