Large-scale PTM analysis reveals that the E3 ligase, Anaphase promoting complex, APC/C, is a master regulator of protein complexes containing GIGYF2.

Large-scale PTM analysis reveals that the E3 ligase, Anaphase promoting complex, APC/C, is a master regulator of protein complexes containing GIGYF2. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Large-scale PTM analysis reveals that the E3 ligase, Anaphase promoting complex, APC/C, is a master regulator of protein complexes containing GIGYF2. Girish N Nallur This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6378554/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract GIGYF2 is one of several uncertain candidates in Parkinson’s disease (PD) since follow-on studies did not confirm the findings from large scale genetics analyses. This report shows that post translational modifications (PTMs) of GIGYF2 and additional proteins or PD candidates with which it complexes are regulated by the E3 ligase Anaphase promoting complex (APC/C) in HEK293T cells. A large-scale screen for PTMs indicates that APC/C employs three distinct modes for recruiting substrates for ubiquitination, including GIGYF2. E3L-tagging interactions of APC/C with HUWE1, UBR4, and CRL4 E3 ligases expands the substrate repertoire to over a thousand proteins. Ubiquitination of enzymes involved in PTMs by APC/C extends its influence over a large section of the proteome. A fifth E3 ligase competes with APC/C for ubiquitination of common substrates, including many proteins implicated in PD. The findings suggest that structural polymorphism of these proteins and the biological environments in which their mutually exclusive complexes function may be responsible for the observed pleiotropy. Consequently, the phenotypic manifestations of GIGYF2 mutations may lie at the intersection of protein structure-function alterations by PTMs and genetic changes involving additional PD candidates. The implications of these findings for target validation and the potential to target APC/C substrates for clinical benefit in PD are discussed. Mass Spectrometry Parkinson's disease GIGYF2 post translational modification E3 ligase APC/C Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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