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EPG5 is a large-sized metazoan protein proposed to serve as a tethering factor to enforce autophagosome\u2013lysosome\/late endosome fusion specificity, and its deficiency causes a severe multisystem disorder known as Vici syndrome. Here, we show that human EPG5 (hEPG5) adopts an extended \u201cshepherd\u2019s staff\u201d architecture. We find that hEPG5 binds preferentially to members of the GABARAP subfamily of human ATG8 proteins critical to autophagosome\u2013lysosome fusion. The hEPG5\u2013GABARAPs interaction, which is mediated by tandem LIR motifs that exhibit differential affinities, is required for hEPG5 recruitment to mitochondria during PINK1\/Parkin-dependent mitophagy. Lastly, we find that the Vici syndrome mutation Gln336Arg does not affect the hEPG5\u2019s overall stability nor its ability to engage in interaction with the GABARAPs. Collectively, results from our studies reveal new insights into how hEPG5 recognizes mature autophagosome and establish a platform for examining the molecular effects of Vici syndrome disease mutations on hEPG5.<\/jats:p>","DOI":"10.1038\/s42003-021-01830-x","type":"journal-article","created":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T11:02:36Z","timestamp":1614942156000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Insights on autophagosome\u2013lysosome tethering from structural and biochemical characterization of human autophagy factor EPG5"],"prefix":"10.1038","volume":"4","author":[{"given":"Sung-Eun","family":"Nam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9698-8479","authenticated-orcid":false,"given":"Yiu Wing Sunny","family":"Cheung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9698-0020","authenticated-orcid":false,"given":"Thanh Ngoc","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2150-5545","authenticated-orcid":false,"given":"Michael","family":"Lazarou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1779-9501","authenticated-orcid":false,"given":"Calvin K.","family":"Yip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,5]]},"reference":[{"key":"1830_CR1","doi-asserted-by":"publisher","first-page":"5037","DOI":"10.1158\/1078-0432.CCR-15-0490","volume":"21","author":"E White","year":"2015","unstructured":"White, E., Mehnert, J. 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