Structural basis for the specificity and catalysis of human Atg4B responsible for mammalian autophagy
- PMID: 16183633
- DOI: 10.1074/jbc.M509158200
Structural basis for the specificity and catalysis of human Atg4B responsible for mammalian autophagy
Abstract
Reversible modification of Atg8 with phosphatidylethanolamine is crucial for autophagy, the bulk degradation system conserved in eukaryotic cells. Atg4 is a novel cysteine protease that processes and deconjugates Atg8. Herein, we report the crystal structure of human Atg4B (HsAtg4B) at 1.9-A resolution. Despite no obvious sequence homology with known proteases, the structure of HsAtg4B shows a classical papain-like fold. In addition to the papain fold region, HsAtg4B has a small alpha/beta-fold domain. This domain is thought to be the binding site for Atg8 homologs. The active site cleft of HsAtg4B is masked by a loop (residues 259-262), implying a conformational change upon substrate binding. The structure and in vitro mutational analyses provide the basis for the specificity and catalysis of HsAtg4B. This will enable the design of Atg4-specific inhibitors that block autophagy.
Similar articles
-
The crystal structure of human Atg4b, a processing and de-conjugating enzyme for autophagosome-forming modifiers.J Mol Biol. 2006 Jan 27;355(4):612-8. doi: 10.1016/j.jmb.2005.11.018. Epub 2005 Nov 28. J Mol Biol. 2006. PMID: 16325851
-
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. doi: 10.1038/emboj.2009.80. Epub 2009 Mar 26. EMBO J. 2009. PMID: 19322194 Free PMC article.
-
HsAtg4B/HsApg4B/autophagin-1 cleaves the carboxyl termini of three human Atg8 homologues and delipidates microtubule-associated protein light chain 3- and GABAA receptor-associated protein-phospholipid conjugates.J Biol Chem. 2004 Aug 27;279(35):36268-76. doi: 10.1074/jbc.M401461200. Epub 2004 Jun 8. J Biol Chem. 2004. PMID: 15187094
-
Targeting Atg4B for cancer therapy: Chemical mediators.Eur J Med Chem. 2021 Jan 1;209:112917. doi: 10.1016/j.ejmech.2020.112917. Epub 2020 Oct 11. Eur J Med Chem. 2021. PMID: 33077263 Review.
-
Unraveling the roles of Atg4 proteases from autophagy modulation to targeted cancer therapy.Cancer Lett. 2016 Apr 1;373(1):19-26. doi: 10.1016/j.canlet.2016.01.022. Epub 2016 Jan 19. Cancer Lett. 2016. PMID: 26805760 Review.
Cited by
-
Post-Translational Modifications of ATG4B in the Regulation of Autophagy.Cells. 2022 Apr 13;11(8):1330. doi: 10.3390/cells11081330. Cells. 2022. PMID: 35456009 Free PMC article. Review.
-
A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B.Sci Rep. 2018 Aug 3;8(1):11653. doi: 10.1038/s41598-018-29900-x. Sci Rep. 2018. PMID: 30076329 Free PMC article.
-
Chemical modulators of autophagy as biological probes and potential therapeutics.Nat Chem Biol. 2011 Jan;7(1):9-17. doi: 10.1038/nchembio.500. Nat Chem Biol. 2011. PMID: 21164513 Review.
-
Total Chemical Synthesis of LC3A and LC3B Activity-Based Probes.Biomedicines. 2023 Mar 13;11(3):884. doi: 10.3390/biomedicines11030884. Biomedicines. 2023. PMID: 36979862 Free PMC article.
-
Biochemical Characterization and Substrate Specificity of Autophagin-2 from the Parasite Trypanosoma cruzi.J Biol Chem. 2015 Nov 20;290(47):28231-28244. doi: 10.1074/jbc.M115.687764. Epub 2015 Oct 7. J Biol Chem. 2015. PMID: 26446788 Free PMC article.
Publication types
MeSH terms
Substances
Associated data
- Actions
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
