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dc.contributor.authorHuber, Jen_US
dc.contributor.authorObata, Men_US
dc.contributor.authorGruber, Jen_US
dc.contributor.authorAkutsu, Men_US
dc.contributor.authorLöhr, Fen_US
dc.contributor.authorRogova, Nen_US
dc.contributor.authorGüntert, Pen_US
dc.contributor.authorDikic, Ien_US
dc.contributor.authorKirkin, Ven_US
dc.contributor.authorKomatsu, Men_US
dc.contributor.authorDötsch, Ven_US
dc.contributor.authorRogov, VVen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2019-04-30T11:00:42Z
dc.date.issued2019-04-16en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/30990354en_US
dc.identifier.citationAutophagy, 2019, pp. 1 - 15en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3210
dc.identifier.eissn1554-8635en_US
dc.identifier.doi10.1080/15548627.2019.1606637en_US
dc.description.abstractShort linear motifs, known as LC3-interacting regions (LIRs), interact with mactoautophagy/autophagy modifiers (Atg8/LC3/GABARAP proteins) via a conserved universal mechanism. Typically, this includes the occupancy of 2 hydrophobic pockets on the surface of Atg8-family proteins by 2 specific aromatic and hydrophobic residues within the LIR motifs. Here, we describe an alternative mechanism of Atg8-family protein interaction with the non-canonical UBA5 LIR, an E1-like enzyme of the ufmylation pathway that preferentially interacts with GABARAP but not LC3 proteins. By solving the structures of both GABARAP and GABARAPL2 in complex with the UBA5 LIR, we show that in addition to the binding to the 2 canonical hydrophobic pockets (HP1 and HP2), a conserved tryptophan residue N-terminal of the LIR core sequence binds into a novel hydrophobic pocket on the surface of GABARAP proteins, which we term HP0. This mode of action is unique for UBA5 and accompanied by large rearrangements of key residues including the side chains of the gate-keeping K46 and the adjacent K/R47 in GABARAP proteins. Swapping mutations in LC3B and GABARAPL2 revealed that K/R47 is the key residue in the specific binding of GABARAP proteins to UBA5, with synergetic contributions of the composition and dynamics of the loop L3. Finally, we elucidate the physiological relevance of the interaction and show that GABARAP proteins regulate the localization and function of UBA5 on the endoplasmic reticulum membrane in a lipidation-independent manner. Abbreviations: ATG: AuTophaGy-related; EGFP: enhanced green fluorescent protein; GABARAP: GABA-type A receptor-associated protein; ITC: isothermal titration calorimetry; KO: knockout; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NMR: nuclear magnetic resonance; RMSD: root-mean-square deviation of atomic positions; TKO: triple knockout; UBA5: ubiquitin like modifier activating enzyme 5.en_US
dc.format.extent1 - 15en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.subjectAutophagyen_US
dc.subjectGABARAPen_US
dc.subjectLC3en_US
dc.subjectLIRen_US
dc.subjectUFM1en_US
dc.subjectcomplex structureen_US
dc.subjectendoplasmic reticulumen_US
dc.subjectpeptide arraysen_US
dc.subjectufmylationen_US
dc.titleAn atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-04-01en_US
rioxxterms.versionofrecord10.1080/15548627.2019.1606637en_US
rioxxterms.licenseref.startdate2019-04-16en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfAutophagyen_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR)
pubs.publication-statusPublished onlineen_US
pubs.embargo.termsNot knownen_US
icr.researchteamCancer Pharmacology & Stress Response (CPSR)en_US
dc.contributor.icrauthorKirkin, Vladimiren_US


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