ATP-dependent Clp protease proteolytic subunit

Caseinolytic mitochondrial matrix peptidase proteolytic subunit
250px PDB rendering based on 1tg6.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1TG6
Identifiers
Symbols	CLPP ; DFNB81; PRLTS3
External IDs	OMIM: 601119 MGI: 1858213 HomoloGene: 4385 GeneCards: CLPP Gene
EC number	3.4.21.92
Gene ontology Molecular function • serine-type endopeptidase activity • protein binding • peptidase activity • identical protein binding Cellular component • mitochondrion • mitochondrial matrix • endopeptidase Clp complex Biological process • protein homooligomerization • proteolysis involved in cellular protein catabolic process Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE CLPP 202799 at tn.png
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	[1]	[2]

ATP-dependent Clp protease proteolytic subunit (ClpP) is an enzyme that in humans is encoded by the CLPP gene. 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. 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.

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

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.

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. 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.

See also

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

External links

• MEROPS entry for ClpP