ClpX

ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial is an enzyme that in humans is encoded by the CLPX gene. This protein is a member of the family of AAA Proteins (AAA+ ATPase) and is to form the protein complex of Clp protease (Endopeptidase Clp).

CLPX
Identifiers
Aliases	CLPX, ClpX, caseinolytic mitochondrial matrix peptidase chaperone subunit, EPP2, caseinolytic mitochondrial matrix peptidase chaperone subunit X
External IDs	OMIM: 615611 MGI: 1346017 HomoloGene: 4851 GeneCards: CLPX
Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q22.31 Start 65,148,219 bp[1] End 65,185,342 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 C|9 35.22 cM Start 65,294,260 bp[2] End 65,330,658 bp[2]
Gene ontology Molecular function • unfolded protein binding • nucleotide binding • GO:0001948 protein binding • peptidase activator activity • metal ion binding • ATP-dependent peptidase activity • ATPase activity • ATP binding Cellular component • mitochondrial endopeptidase Clp complex • mitochondrial matrix • nucleoplasm • endopeptidase Clp complex • mitochondrial nucleoid • mitochondrion • cytosol • mitochondrial inner membrane Biological process • proteolysis involved in cellular protein catabolic process • protein folding • positive regulation of peptidase activity • ATP metabolic process • protein catabolic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	10845	270166
Ensembl	ENSG00000166855	ENSMUSG00000015357
UniProt	O76031	Q9JHS4
RefSeq (mRNA)	NM_006660	NM_001044389 NM_011802
RefSeq (protein)	NP_006651 NP_006651.2	NP_001037854 NP_035932
Location (UCSC)	Chr 15: 65.15 – 65.19 Mb	Chr 9: 65.29 – 65.33 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Protein Structure

The knowledge of human ClpX protein are majorly based on the investigations on E. Coli protein. The monomer of ClpX protein in E. Coli contains a N-terminal domain and a AAA+ module which consists of a large and a small AAA+ domain.[5]

Complex Assembly

During protease Clp complex assembly, the ClpX subunits form a hexameric ring structure. According to the orientation of ClpX subunits within the ring structure, these subunits can be categorized into two classes: "loadable" subunit (L subunit) and "unloadable" subunit (U subunit). In L subunit, the large and small AAA+ domain form a cleft for nucleotide ATP or ADP binding. However, the large and small AAA+ domains in U subunit rotate ~ 80°, which prevents nucleotide binding. The L and U subunits form a "L-L-U-L-L-U" pattern when they assemble into a hexameric ring, which has the maximum capacity to bind four ATP or ADP.[6] Electro-microscopy (EM) studies showed that ClpX ring structures stack coaxially on either one side or both side of ClpP tetradecamer complex to form ClpXP protease complexes. ATP binding can stabilize the association between ClpX and ClpP ring structures.

Function

ClpX is an ATP-dependent chaperone that can recognize protein substrates by binding to protein degradation tags. These tags can be short unstructured peptide sequences (e.g., ssrA-tag in E coli). As an essential component of ClpP protease complex, ClpX recruits degradable substrates and unfolds their tertiary structure, which requires energy provided by ATP hydrolysis. Subsequently, these ClpX Chaperones transfer protein substrates into the proteolytic chamber formed by ClpP tetradecamer.

Clinical Significance

In mammals, ClpXP protease is a pivotal contributor to mitochondrial protein quality control. A compromised ClpXP function usually leads to the accumulation of damaged proteins and mitochondrial dysfunctions, which believes to be potential causes for neurodegenerative diseases and aging.[7]

References

1. GRCh38: Ensembl release 89: ENSG00000166855 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000015357 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Glynn SE, Nager AR, Baker TA, Sauer RT (May 2012). "Dynamic and static components power unfolding in topologically closed rings of a AAA+ proteolytic machine". Nature Structural & Molecular Biology. 19 (6): 616–22. doi:10.1038/nsmb.2288. PMC 3372766. PMID 22562135.
6. Baker TA, Sauer RT (January 2012). "ClpXP, an ATP-powered unfolding and protein-degradation machine". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1823 (1): 15–28. doi:10.1016/j.bbamcr.2011.06.007. PMC 3209554. PMID 21736903.
7. Hamon MP, Bulteau AL, Friguet B (September 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.