Reactome | CLPXP binds mitochondrial matrix proteins

CLPXP binds mitochondrial matrix proteins

Stable Identifier

R-HSA-9838035

Type

Reaction [binding]

Species

Homo sapiens

Compartment

mitochondrial matrix

ReviewStatus

5/5

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CLPXP binds mitochondrial matrix proteins

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The CLPXP complex is an ATP-dependent protease located in the mitochondrial matrix that binds, unfolds, and degrades a specific set of protein substrates. The CLPXP complex comprises two heptameric rings of CLPP protease subunits and two hexameric rings of CLPX ATPase subunits (Kang et al. 2002, 2005). Upon binding the CLPXP complex, substrate proteins are unfolded by CLPX in an ATP-dependent reaction and translocated to the CLPP protease (reviewed in Baker and Sauer 2012, Liu et al. 2014). The CLPXP complex interacts with more than 200 mitochondrial proteins (Cole et al. 2015, Ishizawa et al. 2019, Mabanglo et al. 2022) and degrades several mitochondrial matrix proteins (Lee et al. 2021, Key et al. 2021), including ERAL1, a putative 12S rRNA chaperone (inferred from mouse homologs in Szczepanowska et al. 2016, Key et al. 2022) and heme-bound ALAS1 (Kubota et al. 2016, Nomura et al. 2021). CLPXP can also regulate proteins involved in bioenergetics such as components of the electron transport chain suggesting that it can regulate proteins in the inner mitochondrial membrane (Seo et al. 2016, Ishizawa et al. 2019, Mabanglo et al. 2022). CLPXP is also thought to be involved in the mitochondrial unfolded protein response (inferred from C. elegans homologs in Haynes et al. 2007 and mouse homologs in Lian et al. 2023).

Literature References

PubMed ID	Title	Journal	Year
11923310	Functional proteolytic complexes of the human mitochondrial ATP-dependent protease, hClpXP Kang, SG, Ortega, J, Singh, SK, Wang, N, Huang, NN, Steven, AC, Maurizi, MR	J Biol Chem	2002
34943861	Inactivity of Peptidase ClpP Causes Primary Accumulation of Mitochondrial Disaggregase ClpX with Its Interacting Nucleoid Proteins, and of mtDNA Key, J, Torres-Odio, S, Bach, NC, Gispert, S, Koepf, G, Reichlmeir, M, West, AP, Prokisch, H, Freisinger, P, Newman, WG, Shalev, S, Sieber, SA, Wittig, I, Auburger, G	Cells	2021
31056398	Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality Ishizawa, J, Zarabi, SF, Davis, RE, Halgas, O, Nii, T, Jitkova, Y, Zhao, R, St-Germain, J, Heese, LE, Egan, G, Ruvolo, VR, Barghout, SH, Nishida, Y, Hurren, R, Ma, W, Gronda, M, Link, T, Wong, K, Mabanglo, M, Kojima, K, Borthakur, G, Maclean, N, Ma, MCJ, Leber, AB, Minden, MD, Houry, WA, Kantarjian, H, Stogniew, M, Raught, B, Pai, EF, Schimmer, AD, Andreeff, M	Cancer Cell	2019
22710082	Substrate recognition and processing by a Walker B mutant of the human mitochondrial AAA+ protein CLPX Lowth, BR, Kirstein-Miles, J, Saiyed, T, Brötz-Oesterhelt, H, Morimoto, RI, Truscott, KN, Dougan, DA	J Struct Biol	2012
34704252	Heme-dependent recognition of 5-aminolevulinate synthase by the human mitochondrial molecular chaperone ClpX Nomura, K, Kitagawa, Y, Aihara, M, Ohki, Y, Furuyama, K, Hirokawa, T	FEBS Lett	2021
33637676	LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival Lee, YG, Kim, HW, Nam, Y, Shin, KJ, Lee, YJ, Park, DH, Rhee, HW, Seo, JK, Chae, YC	Oncogenesis	2021
27496948	Novel Mechanisms for Heme-dependent Degradation of ALAS1 Protein as a Component of Negative Feedback Regulation of Heme Biosynthesis Kubota, Y, Nomura, K, Katoh, Y, Yamashita, R, Kaneko, K, Furuyama, K	J Biol Chem	2016
16115876	Human mitochondrial ClpP is a stable heptamer that assembles into a tetradecamer in the presence of ClpX Kang, SG, Dimitrova, MN, Ortega, J, Ginsburg, A, Maurizi, MR	J Biol Chem	2005
26058080	Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia Cole, A, Wang, Z, Coyaud, E, Voisin, V, Gronda, M, Jitkova, Y, Mattson, R, Hurren, R, Babovic, S, Maclean, N, Restall, I, Wang, X, Jeyaraju, DV, Sukhai, MA, Prabha, S, Bashir, S, Ramakrishnan, A, Leung, E, Qia, YH, Zhang, N, Combes, KR, Ketela, T, Lin, F, Houry, WA, Aman, A, Al-Awar, R, Zheng, W, Wienholds, E, Xu, CJ, Dick, J, Wang, JC, Moffat, J, Minden, MD, Eaves, CJ, Bader, GD, Hao, Z, Kornblau, SM, Raught, B, Schimmer, AD	Cancer Cell	2015