{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T14:04:14Z","timestamp":1784297054351,"version":"3.55.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Src-homology-2-containing protein tyrosine phosphatase 2 (SHP2), encoded by the PTPN11 gene, is a master regulator of cell growth, survival, and differentiation. Normally, SHP2 is kept in a self-inhibited state, in which its N-terminal SH2 domain blocks the catalytic site. SHP2 activation is directly tied to the disruption of the self-inhibition. While mutations that disrupt this self-inhibited state can cause developmental disorders and cancer, most SHP2 variants remain functionally uncharacterized. Using computational saturation mutagenesis, we systematically analyzed\u00a0&amp;gt;\u00a09000 single-amino acid substitutions in the SH2 and PTP domains. Our analysis of binding energy changes identified key residues\u2014especially A72 and G503\u2014whose mutation destabilizes the autoinhibited conformation. Functional assays further demonstrated that mutations within the SH2 and PTP domains significantly enhance enzymatic activity, downstream signaling, and cellular proliferation. By integrating clinical data, we found that pathogenic variants preferentially adopt the destabilizing conformations, directly linking structural changes to disease. This work provides a comprehensive map of SHP2 mutation effects, highlights conformational opening as a key driver of pathogenicity, and establishes a predictive framework for interpreting the functional impact of uncharacterized variants in multi-domain proteins.<\/jats:p>","DOI":"10.1093\/jmcb\/mjag022","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T11:47:45Z","timestamp":1784202465000},"source":"Crossref","is-referenced-by-count":0,"title":["Decoding SHP2 mutations by computational saturation mutagenesis"],"prefix":"10.1093","author":[{"given":"Chen","family":"Wang","sequence":"first","affiliation":[{"name":"School of Life Science and Technology, ShanghaiTech University , Shanghai 201210 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, ShanghaiTech University , Shanghai 201210 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaobin","family":"Yao","sequence":"additional","affiliation":[{"name":"Howard University Department of Biology, , 415 College St. NW, Washington, D.C. 20059 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao","family":"Qi","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]},{"name":"Center of Immunological Diseases, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Virology, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxu","family":"Huang","sequence":"additional","affiliation":[{"name":"Research Center for Life Sciences Computing, Zhejiang Lab , Hangzhou ,","place":["China"]},{"name":"The Key Laboratory of Pancreatic Diseases of Zhejiang Province, the First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8326-9889","authenticated-orcid":false,"given":"Shaolei","family":"Teng","sequence":"additional","affiliation":[{"name":"Howard University Department of Biology, , 415 College St. NW, Washington, D.C. 20059 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaofeng","family":"Fan","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, ShanghaiTech University , Shanghai 201210 ,","place":["China"]},{"name":"Shanghai Clinical Research and Trial Center , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,17]]},"container-title":["Journal of Molecular Cell Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jmcb\/advance-article-pdf\/doi\/10.1093\/jmcb\/mjag022\/69162370\/mjag022.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jmcb\/advance-article-pdf\/doi\/10.1093\/jmcb\/mjag022\/69162370\/mjag022.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T13:25:27Z","timestamp":1784294727000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jmcb\/advance-article\/doi\/10.1093\/jmcb\/mjag022\/8736520"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/jmcb\/mjag022","relation":{},"ISSN":["1674-2788","1759-4685"],"issn-type":[{"value":"1674-2788","type":"print"},{"value":"1759-4685","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]},"article-number":"mjag022"}}