ClpX

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CLPX
Identifiers
AliasesCLPX, ClpX, caseinolytic mitochondrial matrix peptidase chaperone subunit, EPP2, caseinolytic mitochondrial matrix peptidase chaperone subunit X
External IDsOMIM: 615611 MGI: 1346017 HomoloGene: 4851 GeneCards: CLPX
Orthologs
SpeciesHumanMouse
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 MbChr 9: 65.2 – 65.24 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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).

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.

In Mycobacteria, the ClpXP protease is composed of the ATPase component (ClpX) and two ClpP proteins (ClpP1 and ClpP2).[7][8] Interestingly, in contrast to the E. coli complex, in which the ATPase component is known to bind to either face of the barrel-shaped peptidase component, in Mycobacteria the ATPase component (ClpX) docks in an asymmetric manner, only binding to a one face of the ClpP1P2 complex - i.e. ClpP2 [9] [10]

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.[11]

References[]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000166855 - Ensembl, May 2017
  2. ^ a b c 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. ^ Akopian T, Kandror O, Raju RM, Unnikrishnan M, Rubin EJ, Goldberg AL (March 2012). "The active ClpP protease from M. tuberculosis is a complex composed of a heptameric ClpP1 and a ClpP2 ring". The EMBO Journal. 31 (6): 1529–41. doi:10.1038/emboj.2012.5. PMC 3321190. PMID 22286948.
  8. ^ Schmitz KR, Carney DW, Sello JK, Sauer RT (October 2014). "Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery". Proceedings of the National Academy of Sciences of the United States of America. 111 (43): E4587-95. Bibcode:2014PNAS..111E4587S. doi:10.1073/pnas.1417120111. PMC 4217457. PMID 25267638.
  9. ^ Leodolter J, Warweg J, Weber-Ban E (2015-05-01). Zeth K (ed.). "The Mycobacterium tuberculosis ClpP1P2 Protease Interacts Asymmetrically with Its ATPase Partners ClpX and ClpC1". PLOS ONE. 10 (5): e0125345. Bibcode:2015PLoSO..1025345L. doi:10.1371/journal.pone.0125345. PMC 4416901. PMID 25933022.
  10. ^ Nagpal J, Paxman JJ, Zammit JE, Alhuwaider A, Truscott KN, Heras B, Dougan DA (December 2019). "Molecular and structural insights into an asymmetric proteolytic complex (ClpP1P2) from Mycobacterium smegmatis". Scientific Reports. 9 (1): 18019. Bibcode:2019NatSR...918019N. doi:10.1038/s41598-019-53736-8. PMC 6889138. PMID 31792243.
  11. ^ 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. S2CID 205667759.
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