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dc.contributor.authorHuber, J
dc.contributor.authorObata, M
dc.contributor.authorGruber, J
dc.contributor.authorAkutsu, M
dc.contributor.authorLöhr, F
dc.contributor.authorRogova, N
dc.contributor.authorGüntert, P
dc.contributor.authorDikic, I
dc.contributor.authorKirkin, V
dc.contributor.authorKomatsu, M
dc.contributor.authorDötsch, V
dc.contributor.authorRogov, VV
dc.date.accessioned2019-04-30T11:00:42Z
dc.date.issued2020-02
dc.identifier.citationAutophagy, 2020, 16 (2), pp. 256 - 270
dc.identifier.issn1554-8627
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3210
dc.identifier.eissn1554-8635
dc.identifier.doi10.1080/15548627.2019.1606637
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.
dc.formatPrint-Electronic
dc.format.extent256 - 270
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.subjectHela Cells
dc.subjectIntracellular Membranes
dc.subjectEndoplasmic Reticulum
dc.subjectHumans
dc.subjectUbiquitin-Activating Enzymes
dc.subjectLysine
dc.subjectPeptides
dc.subjectMicrotubule-Associated Proteins
dc.subjectAmino Acid Sequence
dc.subjectAmino Acid Motifs
dc.subjectProtein Structure, Secondary
dc.subjectProtein Binding
dc.subjectStructure-Activity Relationship
dc.subjectMutation
dc.subjectModels, Molecular
dc.subjectApoptosis Regulatory Proteins
dc.subjectAutophagy-Related Protein 8 Family
dc.titleAn atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5.
dc.typeJournal Article
dcterms.dateAccepted2019-04-01
rioxxterms.versionofrecord10.1080/15548627.2019.1606637
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2020-02
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfAutophagy
pubs.issue2
pubs.notesNot known
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.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
pubs.volume16
pubs.embargo.termsNot known
icr.researchteamCancer Pharmacology & Stress Response (CPSR)en_US
dc.contributor.icrauthorKirkin, Vladimiren


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