ATP-dependent Clp protease proteolytic subunit

Caseinolytic mitochondrial matrix peptidase proteolytic subunit

PDB rendering based on 1tg6.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CLPP ; DFNB81; PRLTS3
External IDs OMIM: 601119 MGI: 1858213 HomoloGene: 4385 GeneCards: CLPP Gene
EC number 3.4.21.92
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 8192 53895
Ensembl ENSG00000125656 ENSMUSG00000002660
UniProt Q16740 O88696
RefSeq (mRNA) NM_006012 NM_017393
RefSeq (protein) NP_006003 NP_059089
Location (UCSC) Chr 19:
6.36 – 6.37 Mb		 Chr 17:
56.99 – 57 Mb
PubMed search

ATP-dependent Clp protease proteolytic subunit (ClpP) is an enzyme that in humans is encoded by the CLPP gene.[1][2] This protein is an essential component to form the protein complex of Clp protease (Endopeptidase Clp).

Protein Structure, Complex Assembly and Heterogeneity

Enzyme ClpP is a highly conserved serine protease present throughout bacterial and also found in the mitochondria and chloroplasts of eukaryotic cells.[3][4] 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.[5]

Functions

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.[6] In several bacteria, such as E. coli, proteins tagged with the SsrA peptide (ANDENYALAA) encoded by tmRNA are digested by Clp proteases.[7]

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.[2]

Clinical Significance

ClpP protease is a major contributor for mitochondrial protein quality control system and removed 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.[8] 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.[9]

See also

References

  1. ↑ 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.
  2. 1 2 "Entrez Gene: CLPP ClpP caseinolytic peptidase, ATP-dependent, proteolytic subunit homolog (E. coli)".
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ Hamon, MP; Bulteau, AL; Friguet, B (8 January 2015). "Mitochondrial proteases and protein quality control in ageing and longevity.". Ageing research reviews 23: 56–66. doi:10.1016/j.arr.2014.12.010. PMID 25578288.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ Luce, K; Weil, AC; Osiewacz, HD (2010). "Mitochondrial protein quality control systems in aging and disease.". Advances in experimental medicine and biology 694: 108–25. PMID 20886760.
  9. ↑ 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

External links


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