{"id":954,"date":"2020-02-12T12:26:37","date_gmt":"2020-02-12T04:26:37","guid":{"rendered":"http:\/\/www.huanglab.org.cn\/wordpress\/?p=954"},"modified":"2020-02-12T12:32:12","modified_gmt":"2020-02-12T04:32:12","slug":"basis-for-metabolite-dependent-cullin-ring-ligase-deneddylation-by-the-cop9-signalosome","status":"publish","type":"post","link":"https:\/\/www.huanglab.org.cn\/wordpress\/?p=954","title":{"rendered":"Basis for metabolite-dependent Cullin-RING ligase deneddylation by the COP9 signalosome"},"content":{"rendered":"\n\n\n<figure class=\"wp-block-image\"><img loading=\"lazy\" width=\"639\" height=\"279\" src=\"http:\/\/www.huanglab.org.cn\/wordpress\/wp-content\/uploads\/2020\/02\/rfs.jpg\" alt=\"\" class=\"wp-image-956\" srcset=\"https:\/\/www.huanglab.org.cn\/wordpress\/wp-content\/uploads\/2020\/02\/rfs.jpg 639w, https:\/\/www.huanglab.org.cn\/wordpress\/wp-content\/uploads\/2020\/02\/rfs-300x131.jpg 300w\" sizes=\"(max-width: 639px) 100vw, 639px\" \/><\/figure>\n\n\n\n<h2>Qiuyu Fu  made important contribution to this study.  <\/h2>\n\n\n\n<p>Hong Lin, Xiaozhe Zhang, Li Liu, Qiuyu Fu, Chuanlong Zang, Yan Ding, Yang Su, Zhixue Xu, Sining He, Xiaoli Yang, Xiayun Wei, Haibin Mao, Yasong Cui, Yi Wei, Chuanzheng Zhou, Lilin Du, Niu Huang, Ning Zheng, Tao Wang, and <a rel=\"noreferrer noopener\" href=\"http:\/\/orcid.org\/0000-0002-6038-6406\" target=\"_blank\"> <\/a>Feng Rao <\/p>\n\n\n\n<h2><\/h2>\n\n\n\n<p><\/p>\n\n\n<h2>Abstract<\/h2>\n\n\n<p>The  Cullin-RING ligases (CRLs) are the largest family of ubiquitin E3s  activated by neddylation and regulated by the deneddylase COP9  signalosome (CSN). The inositol polyphosphate metabolites promote the  formation of CRL\u2013CSN complexes, but with unclear mechanism of action.  Here, we provide structural and genetic evidence supporting inositol  hexakisphosphate (IP<sub>6<\/sub>) as a general CSN cofactor recruiting CRLs. We determined the crystal structure of IP<sub>6<\/sub> in complex with CSN subunit 2 (CSN2), based on which we identified the IP<sub>6<\/sub>-corresponding electron density in the cryoelectron microscopy map of a CRL4A\u2013CSN complex. IP<sub>6<\/sub>  binds to a cognate pocket formed by conserved lysine residues from CSN2  and Rbx1\/Roc1, thereby strengthening CRL\u2013CSN interactions to dislodge  the E2 CDC34\/UBE2R from CRL and to promote CRL deneddylation. IP<sub>6<\/sub> binding-deficient <em>Csn2<\/em><sup><em>K70E\/K70E<\/em><\/sup> knockin mice are embryonic lethal. The same mutation disabled <em>Schizosaccharomyces pombe<\/em> Csn2 from rescuing UV-hypersensitivity of <em>csn2<\/em>-null  yeast. These data suggest that CRL transition from the E2-bound active  state to the CSN-bound sequestered state is critically assisted by an  interfacial IP<sub>6<\/sub> small molecule, whose metabolism may be coupled to CRL\u2013CSN complex dynamics.<\/p>\n\n\n\n<p>\n PNAS first published February 11, 2020 <a href=\"https:\/\/doi.org\/10.1073\/pnas.1911998117\">https:\/\/doi.org\/10.1073\/pnas.1911998117<\/a><\/p>\n\n\n\n<p><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Qiuyu Fu made important contribution to this study. Hong Lin, Xiaozhe Zhang, Li Liu, Qiuyu Fu, Chuanlong Zang, Yan Ding, Yang Su, Zhixue Xu, Sining He, Xiaoli Yang, Xiayun Wei, Haibin Mao, Yasong Cui, Yi Wei, Chuanzheng Zhou, Lilin Du, Niu Huang, Ning Zheng, Tao Wang, and Feng Rao Abstract The Cullin-RING ligases (CRLs) are [&hellip;]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"ngg_post_thumbnail":0},"categories":[10],"tags":[],"_links":{"self":[{"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/954"}],"collection":[{"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=954"}],"version-history":[{"count":13,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/954\/revisions"}],"predecessor-version":[{"id":969,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/954\/revisions\/969"}],"wp:attachment":[{"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=954"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=954"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=954"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}