<\/a>\n\t\t\t<\/div>\n\t\t\t\t<\/a>\n\t\t\t<\/div>\n\t\t\t\tAutophagy<\/h2>\n
One major direction of the group is the structures and functions of protein complexes involved in autophagy. \u00a0Our work begain with the structure of the core of one of these complexes, the class III PI3K,\u00a0Vps34<\/a>.<\/p>\n Autophagy is an ancient process that is present in all eukaryotic cells and it intimately linked with nutrient sensing. The mammalian signalling component of the PI3K pathway is a more recent addition, but it shares intricate connections with autophagy and nutrient sensing. Autophagy acts as a survival mechanism during starvation, and it can act as a quality-control system to remove unneeded organelles or protein aggregates. There is a close connection between autophagy and life span extension, and the process is required for preventing age-related brain degeneration.<\/p>\n Autophagy is associated with cancer, but it is complex and likely to be dependent on the tumour and the stage of its growth. During starvation, the protein kinase mTOR is inactivated. This triggers formation of double membrane vesicles termed autophagosomes that engulf cytosolic material and deliver it to lysosomes for degradation. A large number of genes are involved in autophagy, but work is underway to understand how these genes become engaged in autophagy and how the process is regulated both temporally and spatially (Fig A,\u00a0From Mizushima and Kimatsu (2011) Cell 147, 729<\/a>).<\/p>\n Ttwo protein complexes regulate the iinitial stages of autophagy. One complex that is sometimes callet the “initiation” complex consists of\u00a0the protein kinase ULK1 and its associated subunits, Atg13, Atg101 and FIP200. \u00a0The second complex contains the class III PI3K, Vps34 and three assoxiated proteins, Vps15, beclin and Atg14. \u00a0\u00a0This second complex, sometimes called the “nucleation complex” can give rise to “omegasomes”, which are membrane extensions of the endoplasmic reticulum (ER) enriched in PI3P. \u00a0Within these omegasomes, the first \u00a0 autophagosomes appear and then bud off\u00a0(Fig B, courtesy of\u00a0NIck Ktistakis<\/a>). The initiation complex targets autophagosomal membranes, but its relation to the nucleation complex and the lipid kiase activity of the nucleation complex is still under investigation.<\/p>\n Regulation of phosphoinositide 3-kinases The PI3Ks are activated downstream of receptor tyrosine kinases (RTKs), G-protein coupled receptors (GPCRs) and members of the Ras-superfamily G-proteins. Because these regulatory interactions are specific to individual isoforms, it may be that they represent a useful target for isoform-specific therapeutics. Although we are determining the structures of complexes of these […]<\/p>\n","protected":false},"author":11,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_genesis_hide_title":false,"_genesis_hide_breadcrumbs":false,"_genesis_hide_singular_image":false,"_genesis_hide_footer_widgets":false,"_genesis_custom_body_class":"","_genesis_custom_post_class":"","_genesis_layout":"","footnotes":""},"class_list":{"0":"post-12","1":"page","2":"type-page","3":"status-publish","5":"entry"},"_links":{"self":[{"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/rlw\/wp-json\/wp\/v2\/pages\/12","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/rlw\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/rlw\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/rlw\/wp-json\/wp\/v2\/users\/11"}],"replies":[{"embeddable":true,"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/rlw\/wp-json\/wp\/v2\/comments?post=12"}],"version-history":[{"count":6,"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/rlw\/wp-json\/wp\/v2\/pages\/12\/revisions"}],"predecessor-version":[{"id":56,"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/rlw\/wp-json\/wp\/v2\/pages\/12\/revisions\/56"}],"wp:attachment":[{"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/rlw\/wp-json\/wp\/v2\/media?parent=12"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}<\/p>\n<\/p>\n","protected":false},"excerpt":{"rendered":"