| Structural highlights
Function
[GBRL2_HUMAN] Ubiquitin-like modifier involved in intra-Golgi traffic. Modulates intra-Golgi transport through coupling between NSF activity and SNAREs activation. It first stimulates the ATPase activity of NSF which in turn stimulates the association with GOSR1 (By similarity). Involved in autophagy. Plays a role in mitophagy which contributes to regulate mitochondrial quantity and quality by eliminating the mitochondria to a basal level to fulfill cellular energy requirements and preventing excess ROS production. Whereas LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation.[1] [2] [UBA5_HUMAN] E1-like enzyme which activates UFM1 and SUMO2.[3] [4] [5]
Publication Abstract from PubMed
Short 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.
An atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5.,Huber J, Obata M, Gruber J, Akutsu M, Lohr F, Rogova N, Guntert P, Dikic I, Kirkin V, Komatsu M, Dotsch V, Rogov VV Autophagy. 2019 Apr 16:1-15. doi: 10.1080/15548627.2019.1606637. PMID:30990354[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Weidberg H, Shvets E, Shpilka T, Shimron F, Shinder V, Elazar Z. LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis. EMBO J. 2010 Jun 2;29(11):1792-802. doi: 10.1038/emboj.2010.74. Epub 2010 Apr 23. PMID:20418806 doi:http://dx.doi.org/10.1038/emboj.2010.74
- ↑ Zhu Y, Massen S, Terenzio M, Lang V, Chen-Lindner S, Eils R, Novak I, Dikic I, Hamacher-Brady A, Brady NR. Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis. J Biol Chem. 2013 Jan 11;288(2):1099-113. doi: 10.1074/jbc.M112.399345. Epub 2012, Dec 3. PMID:23209295 doi:http://dx.doi.org/10.1074/jbc.M112.399345
- ↑ Komatsu M, Chiba T, Tatsumi K, Iemura S, Tanida I, Okazaki N, Ueno T, Kominami E, Natsume T, Tanaka K. A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. EMBO J. 2004 May 5;23(9):1977-86. Epub 2004 Apr 8. PMID:15071506 doi:http://dx.doi.org/10.1038/sj.emboj.7600205
- ↑ Zheng M, Gu X, Zheng D, Yang Z, Li F, Zhao J, Xie Y, Ji C, Mao Y. UBE1DC1, an ubiquitin-activating enzyme, activates two different ubiquitin-like proteins. J Cell Biochem. 2008 Aug 15;104(6):2324-34. doi: 10.1002/jcb.21791. PMID:18442052 doi:http://dx.doi.org/10.1002/jcb.21791
- ↑ Bacik JP, Walker JR, Ali M, Schimmer AD, Dhe-Paganon S. Crystal structure of the human ubiquitin-activating enzyme 5 (UBA5) bound to ATP: mechanistic insights into a minimalistic E1 enzyme. J Biol Chem. 2010 Jun 25;285(26):20273-80. Epub 2010 Apr 5. PMID:20368332 doi:10.1074/jbc.M110.102921
- ↑ Huber J, Obata M, Gruber J, Akutsu M, Lohr F, Rogova N, Guntert P, Dikic I, Kirkin V, Komatsu M, Dotsch V, Rogov VV. An atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5. Autophagy. 2019 Apr 16:1-15. doi: 10.1080/15548627.2019.1606637. PMID:30990354 doi:http://dx.doi.org/10.1080/15548627.2019.1606637
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