ATP-dependent Clp protease proteolytic subunit

ATP-dependent Clp protease proteolytic subunit (ClpP) is an enzyme that in humans is encoded by the CLPP gene.[4][5] This protein is an essential component to form the protein complex of Clp protease (Endopeptidase Clp).

CLPP
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1TG6
Identifiers
Aliases	CLPP, PRLTS3, DFNB81, caseinolytic mitochondrial matrix peptidase proteolytic subunit
External IDs	OMIM: 601119 MGI: 1858213 HomoloGene: 4385 GeneCards: CLPP
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19p13.3 Start 6,361,531 bp[1] End 6,370,242 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • peptidase activity • serine-type peptidase activity • serine-type endopeptidase activity • GO:0001948 protein binding • hydrolase activity • identical protein binding • ATP-dependent peptidase activity • ATPase binding Cellular component • mitochondrial matrix • mitochondrion • endopeptidase Clp complex Biological process • proteolysis involved in cellular protein catabolic process • protein homooligomerization • proteolysis • protein quality control for misfolded or incompletely synthesized proteins Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	8192	53895
Ensembl	ENSG00000125656	n/a
UniProt	Q16740	O88696
RefSeq (mRNA)	NM_006012	NM_017393
RefSeq (protein)	NP_006003	NP_059089
Location (UCSC)	Chr 19: 6.36 – 6.37 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Enzyme ClpP is a highly conserved serine protease present throughout bacterial and also found in the mitochondria and chloroplasts of eukaryotic cells.[6][7] The ClpP monomer is folded into three subdomains: the "handle", the globular "head", and the N-terminal region. By itself, ClpP can assemble into a tetradecamer complex (14-members) and form a closed proteolytic chamber. A fully assembled Clp protease complex has a barrel-shaped structure in which two stacked ring of proteolytic subunits (ClpP or ClpQ) are either sandwiched between two rings or single-caped by one ring of ATPase-active chaperon subunits (ClpA, ClpC, ClpE, ClpX or ClpY). ClpXP is presented in almost all bacteria while ClpA is found in the Gram-negative bacteria, ClpC in Gram-Positive bacteria and cyanobacteria. ClpAP, ClpXP and ClpYQ coexist in E. Coli while only ClpXP complex in present in humans.[8]

Function

In bacteria, it was shown that ClpP is capable to cleave full-length proteins without being associated with ClpA but the degradation is at a much slower rate. Fully functional Clp protease requires the participation of AAA+ ATPase. These ClpX chaperons recognize, unfold and transfer protein substrates to proteolytic core formed by ClpP tetradecamer. The proteolytic sites of ClpP subunits contain hydrophobic grooves which recruit substrate and host the catalytic triad Asp-His-Ser.[9] In several bacteria, such as E. coli, proteins tagged with the SsrA peptide (ANDENYALAA) encoded by tmRNA are digested by Clp proteases.[10]

The protein encoded by this gene belongs to the peptidase family S14 and hydrolyzes proteins into small peptides in the presence of ATP and magnesium. The protein is transported into mitochondrial matrix and is associated with the inner mitochondrial membrane.[5]

Clinical Significance

ClpP protease is a major contributor for mitochondrial protein quality control system and removing damaged or misfolded proteins in mitochondrial matrix. Defects in mitochondrial Clp proteases have been associated with the progression of neurodegenerative diseases while upregulation of ClpP proteases has been implicated in preventing premature aging.[11] Recessive CLPP mutations were recently observed in the human Perrault variant associating with ovarian failure and sensorineural hearing loss, in parallel with growth retardation. The clinical phenotype was accompanied by the accumulation of ClpP associating partner chaperon ClpX, mtRNA, and inflammatory factors. The disease pathological cause probably involves deficient clearance of mitochondrial components and inflammatory tissue destruction.[12]

See also

• CLP protease family
• Endopeptidase Clp
• Protease
• Transfer-messenger RNA

References

1. GRCh38: Ensembl release 89: ENSG00000125656 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. Bross P, Andresen BS, Knudsen I, Kruse TA, Gregersen N (Feb 1996). "Human ClpP protease: cDNA sequence, tissue-specific expression and chromosomal assignment of the gene". FEBS Lett. 377 (2): 249–52. doi:10.1016/0014-5793(95)01353-9. PMID 8543061.
5. "Entrez Gene: CLPP ClpP caseinolytic peptidase, ATP-dependent, proteolytic subunit homolog (E. coli)".
6. Katayama-Fujimura, Y; Gottesman, S; Maurizi, MR (5 April 1987). "A multiple-component, ATP-dependent protease from Escherichia coli". The Journal of Biological Chemistry. 262 (10): 4477–85. PMID 3549708.
7. Corydon, TJ; Bross, P; Holst, HU; Neve, S; Kristiansen, K; Gregersen, N; Bolund, L (1 April 1998). "A human homologue of Escherichia coli ClpP caseinolytic protease: recombinant expression, intracellular processing and subcellular localization". The Biochemical Journal. 331 (1): 309–16. doi:10.1042/bj3310309. PMC 1219353. PMID 9512494.
8. Hamon, MP; Bulteau, AL; Friguet, B (8 January 2015). "Mitochondrial proteases and protein quality control in ageing and longevity". Ageing Research Reviews. 23 (Pt A): 56–66. doi:10.1016/j.arr.2014.12.010. PMID 25578288.
9. Wang, J; Hartling, JA; Flanagan, JM (14 November 1997). "The structure of ClpP at 2.3 A resolution suggests a model for ATP-dependent proteolysis". Cell. 91 (4): 447–56. doi:10.1016/s0092-8674(00)80431-6. PMID 9390554.
10. Gottesman S, Roche E, Zhou Y, Sauer RT (1998). "The ClpXP and ClpAP proteases degrade proteins with carboxy-terminal peptide tails added by the SsrA-tagging system". Genes Dev. 12 (9): 1338–47. doi:10.1101/gad.12.9.1338. PMC 316764. PMID 9573050.
11. Luce, K; Weil, AC; Osiewacz, HD (2010). Mitochondrial protein quality control systems in aging and disease. Advances in Experimental Medicine and Biology. 694. pp. 108–25. doi:10.1007/978-1-4419-7002-2_9. ISBN 978-1-4419-7001-5. PMID 20886760.
12. Gispert, S; Parganlija, D; Klinkenberg, M; Dröse, S; Wittig, I; Mittelbronn, M; Grzmil, P; Koob, S; Hamann, A; Walter, M; Büchel, F; Adler, T; Hrabé de Angelis, M; Busch, DH; Zell, A; Reichert, AS; Brandt, U; Osiewacz, HD; Jendrach, M; Auburger, G (15 December 2013). "Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA and inflammatory factors". Human Molecular Genetics. 22 (24): 4871–87. doi:10.1093/hmg/ddt338. PMID 23851121.

Further reading

• Kang SG, Dimitrova MN, Ortega J, et al. (2005). "Human mitochondrial ClpP is a stable heptamer that assembles into a tetradecamer in the presence of ClpX". J. Biol. Chem. 280 (42): 35424–32. doi:10.1074/jbc.M507240200. PMID 16115876.
• Kang SG, Maurizi MR, Thompson M, et al. (2005). "Crystallography and mutagenesis point to an essential role for the N-terminus of human mitochondrial ClpP". J. Struct. Biol. 148 (3): 338–52. doi:10.1016/j.jsb.2004.07.004. PMID 15522782.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Kang SG, Ortega J, Singh SK, et al. (2002). "Functional proteolytic complexes of the human mitochondrial ATP-dependent protease, hClpXP". J. Biol. Chem. 277 (23): 21095–102. doi:10.1074/jbc.M201642200. PMID 11923310.
• de Sagarra MR, Mayo I, Marco S, et al. (1999). "Mitochondrial localization and oligomeric structure of HClpP, the human homologue of E. coli ClpP". J. Mol. Biol. 292 (4): 819–25. doi:10.1006/jmbi.1999.3121. PMID 10525407.
• Corydon TJ, Bross P, Holst HU, et al. (1998). "A human homologue of Escherichia coli ClpP caseinolytic protease: recombinant expression, intracellular processing and subcellular localization". Biochem. J. 331 (Pt 1): 309–16. doi:10.1042/bj3310309. PMC 1219353. PMID 9512494.

External links

• MEROPS entry for ClpP
• Human CLPP genome location and CLPP gene details page in the UCSC Genome Browser.