| Structural highlights
Function
[GBRL1_HUMAN] Increases cell-surface expression of kappa-type opioid receptor through facilitating anterograde intracellular trafficking of the receptor. Involved in formation of autophagosomal vacuoles.[1] [2] [ATG4B_HUMAN] Cysteine protease required for autophagy, which cleaves the C-terminal part of MAP1LC3, GABARAPL1, GABARAPL2 and GABARAP, allowing the liberation of form I. A subpopulation of form I is subsequently converted to a smaller form (form II). Form II, with a revealed C-terminal glycine, is considered to be the phosphatidylethanolamine (PE)-conjugated form, and has the capacity for the binding to autophagosomes. Also mediates the lipid deconjugation required for target recycling.[3] [4]
Publication Abstract from PubMed
The cysteine protease ATG4B cleaves off one or more C-terminal residues of the inactive proform of proteins of the ortholog and paralog LC3 and GABARAP subfamilies of yeast Atg8 to expose a C-terminal glycine that is conjugated to phosphatidylethanolamine during autophagosome formation. We show that ATG4B contains a C-terminal LC3-interacting region (LIR) motif important for efficient binding to and cleavage of LC3 and GABARAP proteins. We solved the crystal structures of the GABARAPL1-ATG4B C-terminal LIR complex. Analyses of the structures and in vitro binding assays, using specific point mutants, clearly showed that the ATG4B LIR binds via electrostatic-, aromatic HP1 and hydrophobic HP2 pocket interactions. Both these interactions and the catalytic site-substrate interaction contribute to binding between LC3s or GABARAPs and ATG4B. We also reveal an unexpected role for ATG4B in stabilizing the unlipidated forms of GABARAP and GABARAPL1. In mouse embryonic fibroblast (MEF) atg4b knockout cells, GABARAP and GABARAPL1 were unstable and degraded by the proteasome. Strikingly, the LIR motif of ATG4B was required for stabilization of the unlipidated forms of GABARAP and GABARAPL1 in cells.
ATG4B contains a C-terminal LIR motif important for binding and efficient cleavage of mammalian orthologs of yeast Atg8.,Skytte Rasmussen M, Mouilleron S, Kumar Shrestha B, Wirth M, Lee R, Bowitz Larsen K, Abudu Princely Y, O'Reilly N, Sjottem E, Tooze SA, Lamark T, Johansen T Autophagy. 2017 Feb 15:1-20. doi: 10.1080/15548627.2017.1287651. PMID:28287329[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chen C, Li JG, Chen Y, Huang P, Wang Y, Liu-Chen LY. GEC1 interacts with the kappa opioid receptor and enhances expression of the receptor. J Biol Chem. 2006 Mar 24;281(12):7983-93. Epub 2006 Jan 23. PMID:16431922 doi:M509805200
- ↑ Chakrama FZ, Seguin-Py S, Le Grand JN, Fraichard A, Delage-Mourroux R, Despouy G, Perez V, Jouvenot M, Boyer-Guittaut M. GABARAPL1 (GEC1) associates with autophagic vesicles. Autophagy. 2010 May;6(4):495-505. doi: 10.4161/auto.6.4.11819. Epub 2010 May 16. PMID:20404487 doi:10.4161/auto.6.4.11819
- ↑ Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J Cell Sci. 2004 Jun 1;117(Pt 13):2805-12. PMID:15169837 doi:10.1242/jcs.01131
- ↑ Satoo K, Noda NN, Kumeta H, Fujioka Y, Mizushima N, Ohsumi Y, Inagaki F. The structure of Atg4B-LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy. EMBO J. 2009 May 6;28(9):1341-50. Epub 2009 Mar 26. PMID:19322194 doi:10.1038/emboj.2009.80
- ↑ Skytte Rasmussen M, Mouilleron S, Kumar Shrestha B, Wirth M, Lee R, Bowitz Larsen K, Abudu Princely Y, O'Reilly N, Sjottem E, Tooze SA, Lamark T, Johansen T. ATG4B contains a C-terminal LIR motif important for binding and efficient cleavage of mammalian orthologs of yeast Atg8. Autophagy. 2017 Feb 15:1-20. doi: 10.1080/15548627.2017.1287651. PMID:28287329 doi:http://dx.doi.org/10.1080/15548627.2017.1287651
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