| Structural highlights
Function
LONM_HUMAN ATP-dependent serine protease that mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides as well as certain short-lived regulatory proteins in the mitochondrial matrix. May also have a chaperone function in the assembly of inner membrane protein complexes. Participates in the regulation of mitochondrial gene expression and in the maintenance of the integrity of the mitochondrial genome. Binds to mitochondrial promoters and RNA in a single-stranded, site-specific, and strand-specific manner. May regulate mitochondrial DNA replication and/or gene expression using site-specific, single-stranded DNA binding to target the degradation of regulatory proteins binding to adjacent sites in mitochondrial promoters. Endogenous substrates include mitochondrial steroidogenic acute regulatory (StAR) protein.[HAMAP-Rule:MF_03120][1] [2] [3] [4]
Publication Abstract from PubMed
The mitochondrial Lon protease (LonP1) regulates mitochondrial health by removing redundant proteins from the mitochondrial matrix. We determined LonP1 in eight nucleotide-dependent conformational states by cryoelectron microscopy (cryo-EM). The flexible assembly of N-terminal domains had 3-fold symmetry, and its orientation depended on the conformational state. We show that a conserved structural motif around T803 with a high similarity to the trypsin catalytic triad is essential for proteolysis. We show that LonP1 is not regulated by redox potential, despite the presence of two conserved cysteines at disulfide-bonding distance in its unfoldase core. Our data indicate how sequential ATP hydrolysis controls substrate protein translocation in a 6-fold binding change mechanism. Substrate protein translocation, rather than ATP hydrolysis, is a rate-limiting step, suggesting that LonP1 is a Brownian ratchet with ATP hydrolysis preventing translocation reversal. 3-fold rocking motions of the flexible N-domain assembly may assist thermal unfolding of the substrate protein.
Catalytic cycling of human mitochondrial Lon protease.,Mohammed I, Schmitz KA, Schenck N, Balasopoulos D, Topitsch A, Maier T, Abrahams JP Structure. 2022 Sep 1;30(9):1254-1268.e7. doi: 10.1016/j.str.2022.06.006. Epub , 2022 Jul 22. PMID:35870450[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bota DA, Davies KJ. Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism. Nat Cell Biol. 2002 Sep;4(9):674-80. PMID:12198491 doi:http://dx.doi.org/10.1038/ncb836
- ↑ Ondrovicova G, Liu T, Singh K, Tian B, Li H, Gakh O, Perecko D, Janata J, Granot Z, Orly J, Kutejova E, Suzuki CK. Cleavage site selection within a folded substrate by the ATP-dependent lon protease. J Biol Chem. 2005 Jul 1;280(26):25103-10. Epub 2005 May 3. PMID:15870080 doi:http://dx.doi.org/10.1074/jbc.M502796200
- ↑ Lu B, Yadav S, Shah PG, Liu T, Tian B, Pukszta S, Villaluna N, Kutejova E, Newlon CS, Santos JH, Suzuki CK. Roles for the human ATP-dependent Lon protease in mitochondrial DNA maintenance. J Biol Chem. 2007 Jun 15;282(24):17363-74. Epub 2007 Apr 9. PMID:17420247 doi:http://dx.doi.org/10.1074/jbc.M611540200
- ↑ Wang N, Gottesman S, Willingham MC, Gottesman MM, Maurizi MR. A human mitochondrial ATP-dependent protease that is highly homologous to bacterial Lon protease. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11247-51. PMID:8248235
- ↑ Mohammed I, Schmitz KA, Schenck N, Balasopoulos D, Topitsch A, Maier T, Abrahams JP. Catalytic cycling of human mitochondrial Lon protease. Structure. 2022 Jul 12. pii: S0969-2126(22)00269-6. doi:, 10.1016/j.str.2022.06.006. PMID:35870450 doi:http://dx.doi.org/10.1016/j.str.2022.06.006
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