ClpX

Last updated
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
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 Mb Chr 9: 65.2 – 65.24 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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).

Contents

Structure

Tertiary

The human enzyme ClpX is drawn from the protein complex structure of Clp protease. These hexameric HSP100/Clp proteins produce ring like structures resembling chaperonins. [5]

Molecular structure of protein registered with ClpX PDB 1fcd EBI.jpg
Molecular structure of protein registered with ClpX
Proteasome evolution showing step-wise increase in complexity. Rooting-the-tree-of-life-by-transition-analyses-1745-6150-1-19-5.jpg
Proteasome evolution showing step-wise increase in complexity.

The Clp proteases have a two-component structure which includes two different proteolytic cores and multiple chaperone rings. As a result, there are several possible combinations of Clp protease complexes. The ClpP protease core can partner with different chaperones, namely ClpA, ClpC, ClpE, and ClpX, to form active chaperone-protease complexes. On the other hand, ClpQ interacts exclusively with the ClpY chaperone to form the ClpYQ protease (also called HslUV) . The Clp-type ATPases can be classified into two distinct groups: class I with two consecutive AAA modules per protomer(ClpA, ClpC, and ClpE) and class II with only one AAA module per protomer. [6]

ClpA and ClpX of E. coli are protein unfoldases that require ATP to function. They individually associate with the ClpP protease to facilitate targeted protein degradation. [7] These variants have inflicted variants interspecific with ClpP.

Quaternary

The complex assembly of the regulatory subunits of ATP-dependent Clp proteases is induced in the critical role in cellular thermotolerance. There are numerous proteases that are thought to have a bacterial origin. Studies on the protein of E. coli are the main source of information about the human ClpX protein. In E. coli, the ClpX protein monomer has an N-terminal domain and a AAA+ module made up of two AAA+ domains, one larger than the other. [8] Since the prevalence of E.coli is at such a high factor in most people around the world, the constitutive aspect of ClpX showed multiple signs in research of the protease.

Clp protease is made up of ATPase-active chaperone rings and a proteolytic core, two functional units with distinct functions that play a role in cellular thermotolerance. [9] [10] The ClpXP chaperone-protease is present in almost every type of bacteria, commonly found together with the widely distributed Lon and FtsH proteases. Hence, ClpXP is the most prevalent among the Clp. [11]

The HslV rings engage with an unrelated chaperone ATPase called HslU, which also has 6-fold ring symmetry. This is similar to the ClpX chaperone, which it potentially evolved from, and almost all AAA+ ATPase proteins that emerged from a surge of gene duplications prior to the last common ancestor of all life. This allows the assumption that most mammals from the common ancestors between humans and mice were shown to have this relating enzyme. As shown on the infobox gene similarity between a mouse and a human, we can distinctly see its similarities and differences in the Clp protease.

Function

Bacteria use the ATP-dependent ClpX protease for a variety of purposes, including protein quality control, stress tolerance, the production of virulence factors, and binding to protein degradation tags in E.coli. The ATPase component is in charge of substrate recognition, unfolding, and transport into the proteolytic component. The proteolytic component has several serine- or threonine-type active sites that allow for protein hydrolysis. [12] Accordingly, it seems that depending on the physiological circumstances, clpX can either be produced alone or in conjunction with clpP in cells. [13] ClpX and ClpP are two proteins that work together in the ClpXP complex, which is a major protein degradation system in bacteria. ClpX is an ATPase that provides the energy for unfolding and translocating target proteins into the ClpP protease for degradation. ClpP is the protease that cleaves the unfolded target proteins.

The function of the ClpX has several complexity factors that can be seen in the proteasome evolution figure. This shows the evolution of proteasomes that has occurred in a stepwise manner, with increasing complexity over time. The first step was the development of the HslV ring protease, followed by the 20S proteasome, and finally, the 26S proteasome. Grey bars on the evolutionary tree represent the two significant transitions in proteasome structure that are crucial for polarizing the tree. Additionally, four other evolutionary transitions are marked by blue bars that also align with the tree's polarization. The HslV ring protease has 6-fold symmetry, with a 2-tiered ring consisting of 12 identical subunits. It is believed to have arisen from a monomeric NTN hydrolase, possibly just before the divergence of Hadobacteria. [14] The regulation of ClpX and ClpP expression is complex and involves various factors, including transcriptional regulators, environmental signals, and post-transcriptional modifications. Understanding how the expression of these proteins is regulated can provide insights into the mechanisms by which bacteria respond to stress and maintain cellular homeostasis.

Clinical significance

The mitochondrial system responsible for maintaining protein quality, especially clpx, plays a crucial role in influencing fertility, survival, and neural aging. [15] Studies have indicated that improper regulation of the protein quality control system within the mitochondria, which includes the CLPXP complex, can significantly impact cellular health and function. For instance, when researchers deleted the CLPP subunit in mice, they observed a decline in fertility and a rise in early embryonic mortality. These findings suggest that the clpx complex plays a crucial role in maintaining appropriate mitochondrial function during gamete production and embryonic development.

The ClpXP protease is a significant player in mitochondrial protein quality control in mammals. When ClpXP function is compromised, it can result in the accumulation of damaged proteins and mitochondrial malfunctions. These issues are believed to be potential causes of neurodegenerative diseases and aging. Having such a variety of Clp complexes, the insight of the ClpX assembly is crucial to identify any detrimental damages in humans for long term issues or term. Having a common ancestor with mice allows for future studies to be developed in understanding this enzyme.

Through extensive research of E.coli with correlation to ClpXp, research on Mycobacterium tuberculosis took place. The data revealed that ClpX participates in DNA replication and identify the first activator of ClpXp in mycobacteria as well. [16] This knowledge correlates with research of when ClpX is inhibited, the bacterium became more susceptible to antibiotics. This suggests that targeting ClpX could be a strategy for overcoming antibiotic resistance in bacterial infections in this research. However, the research is ongoing and more definitive results are needed to take place.

Related Research Articles

<span class="mw-page-title-main">Proteasome</span> Protein complexes which degrade unnecessary or damaged proteins by proteolysis

Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.

<span class="mw-page-title-main">AAA proteins</span> Protein family

AAAproteins are a large group of protein family sharing a common conserved module of approximately 230 amino acid residues. This is a large, functionally diverse protein family belonging to the AAA+ protein superfamily of ring-shaped P-loop NTPases, which exert their activity through the energy-dependent remodeling or translocation of macromolecules.

<span class="mw-page-title-main">Endopeptidase Clp</span>

Endopeptidase Clp (EC 3.4.21.92, endopeptidase Ti, caseinolytic protease, protease Ti, ATP-dependent Clp protease, ClpP, Clp protease). This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">HslVU</span> Class of bacterial heat shock proteins

The heat shock proteins HslV and HslU are expressed in many bacteria such as E. coli in response to cell stress. The hslV protein is a protease and the hslU protein is an ATPase; the two form a symmetric assembly of four stacked rings, consisting of an hslV dodecamer bound to an hslU hexamer, with a central pore in which the protease and ATPase active sites reside. The hslV protein degrades unneeded or damaged proteins only when in complex with the hslU protein in the ATP-bound state. HslV is thought to resemble the hypothetical ancestor of the proteasome, a large protein complex specialized for regulated degradation of unneeded proteins in eukaryotes, many archaea, and a few bacteria. HslV bears high similarity to core subunits of proteasomes.

<span class="mw-page-title-main">PSMC3</span> Enzyme found in humans

26S protease regulatory subunit 6A, also known as 26S proteasome AAA-ATPase subunit Rpt5, is an enzyme that in humans is encoded by the PSMC3 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMD5</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 5 is an enzyme that in humans is encoded by the PSMD5 gene.

<span class="mw-page-title-main">PSMC5</span> Enzyme found in humans

26S protease regulatory subunit 8, also known as 26S proteasome AAA-ATPase subunit Rpt6, is an enzyme that in humans is encoded by the PSMC5 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMD4</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 4, also as known as 26S Proteasome Regulatory Subunit Rpn10, is an enzyme that in humans is encoded by the PSMD4 gene. This protein is one of the 19 essential subunits that contributes to the complete assembly of 19S proteasome complex.

<span class="mw-page-title-main">PSMC2</span> Enzyme found in humans

26S protease regulatory subunit 7, also known as 26S proteasome AAA-ATPase subunit Rpt1, is an enzyme that in humans is encoded by the PSMC2 gene This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex. Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMC1</span> Enzyme found in humans

26S protease regulatory subunit 4, also known as 26S proteasome AAA-ATPase subunit Rpt2, is an enzyme that in humans is encoded by the PSMC1 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex. Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMC4</span> Enzyme found in humans

26S protease regulatory subunit 6B, also known as 26S proteasome AAA-ATPase subunit Rpt3, is an enzyme that in humans is encoded by the PSMC4 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMD7</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 7, also known as 26S proteasome non-ATPase subunit Rpn8, is an enzyme that in humans is encoded by the PSMD7 gene.

<span class="mw-page-title-main">PSMC6</span> Enzyme found in humans

26S protease regulatory subunit S10B, also known as 26S proteasome AAA-ATPase subunit Rpt4, is an enzyme that in humans is encoded by the PSMC6 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMD1</span> Protein found in humans

26S proteasome non-ATPase regulatory subunit 1, also as known as 26S Proteasome Regulatory Subunit Rpn2, is a protein that in humans is encoded by the PSMD1 gene. This protein is one of the 19 essential subunits that contributes to the complete assembly of 19S proteasome complex.

<span class="mw-page-title-main">PSMD2</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 2, also as known as 26S Proteasome Regulatory Subunit Rpn1, is an enzyme that in humans is encoded by the PSMD2 gene.

<span class="mw-page-title-main">LONP1</span> Human protein and coding gene

Lon protease homolog, mitochondrial is a protease, an enzyme that in humans is encoded by the LONP1 gene.

<span class="mw-page-title-main">PSMD14</span> Protein-coding gene in the species Homo sapiens

26S proteasome non-ATPase regulatory subunit 14, also known as 26S proteasome non-ATPase subunit Rpn11, is an enzyme that in humans is encoded by the PSMD14 gene. This protein is one of the 19 essential subunits of the complete assembled 19S proteasome complex. Nine subunits Rpn3, Rpn5, Rpn6, Rpn7, Rpn8, Rpn9, Rpn11, SEM1, and Rpn12 form the lid sub complex of the 19S regulatory particle of the proteasome complex.

<span class="mw-page-title-main">CLPB</span> Protein-coding gene in the species Homo sapiens

Caseinolytic peptidase B protein homolog (CLPB), also known as Skd3, is a mitochondrial AAA ATPase chaperone that in humans is encoded by the gene CLPB, which encodes an adenosine triphosphate-(ATP) dependent chaperone. Skd3 is localized in mitochondria and widely expressed in human tissues. High expression in adult brain and low expression in granulocyte is found. It is a potent protein disaggregase that chaperones the mitochondrial intermembrane space. Mutations in the CLPB gene could cause autosomal recessive metabolic disorder with intellectual disability/developmental delay, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria. Recently, heterozygous, dominant negative mutations in CLPB have been identified as a cause of severe congenital neutropenia (SCN).

<span class="mw-page-title-main">ATP-dependent Clp protease proteolytic subunit</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Clp protease family</span> A protein-targeting ATP-dependent enzyme family.

In molecular biology, the CLP protease family is a family of serine peptidases belong to the MEROPS peptidase family S14. ClpP is an ATP-dependent protease that cleaves a number of proteins, such as casein and albumin. It exists as a heterodimer of ATP-binding regulatory A and catalytic P subunits, both of which are required for effective levels of protease activity in the presence of ATP, although the P subunit alone does possess some catalytic activity.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000166855 – Ensembl, May 2017
  2. 1 2 3 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. ↑ van Dyck L, Dembowski M, Neupert W, Langer T (November 1998). "Mcx1p, a ClpX homologue in mitochondria of Saccharomyces cerevisiae". FEBS Letters. 438 (3): 250–254. Bibcode:1998FEBSL.438..250V. doi: 10.1016/s0014-5793(98)01310-6 . PMID   9827555.
  6. ↑ Singh SK, Rozycki J, Ortega J, Ishikawa T, Lo J, Steven AC, Maurizi MR (August 2001). "Functional domains of the ClpA and ClpX molecular chaperones identified by limited proteolysis and deletion analysis". The Journal of Biological Chemistry. 276 (31): 29420–29429. doi: 10.1074/jbc.M103489200 . PMID   11346657.
  7. ↑ Gottesman S, Clark WP, de Crecy-Lagard V, Maurizi MR (October 1993). "ClpX, an alternative subunit for the ATP-dependent Clp protease of Escherichia coli. Sequence and in vivo activities". The Journal of Biological Chemistry. 268 (30): 22618–22626. doi: 10.1016/S0021-9258(18)41573-6 . PMID   8226770.
  8. ↑ Halperin T, Zheng B, Itzhaki H, Clarke AK, Adam Z (March 2001). "Plant mitochondria contain proteolytic and regulatory subunits of the ATP-dependent Clp protease". Plant Molecular Biology. 45 (4): 461–468. doi:10.1023/A:1010677220323. PMID   11352464.
  9. ↑ Schmidt R, Bukau B, Mogk A (November 2009). "Principles of general and regulatory proteolysis by AAA+ proteases in Escherichia coli". Research in Microbiology. 160 (9): 629–36. doi: 10.1016/j.resmic.2009.08.018 . PMID   19781640.
  10. ↑ Kress W, Maglica Z, Weber-Ban E (November 2009). "Clp chaperone-proteases: structure and function". Research in Microbiology. 160 (9): 618–28. doi: 10.1016/j.resmic.2009.08.006 . PMID   19732826.
  11. ↑ Kress W, Maglica Z, Weber-Ban E (November 2009). "Clp chaperone-proteases: structure and function". Research in Microbiology. Special issue on proteolysis in prokaryotes: protein quality control and regulatory principles. 160 (9): 618–628. doi: 10.1016/j.resmic.2009.08.006 . PMID   19732826.
  12. ↑ Kress W, Maglica Z, Weber-Ban E (November 2009). "Clp chaperone-proteases: structure and function". Research in Microbiology. Special issue on proteolysis in prokaryotes: protein quality control and regulatory principles. 160 (9): 618–628. doi: 10.1016/j.resmic.2009.08.006 . PMID   19732826.
  13. ↑ Yoo SJ, Seol JH, Kang MS, Ha DB, Chung CH (September 1994). "clpX encoding an alternative ATP-binding subunit of protease Ti (Clp) can be expressed independently from clpP in Escherichia coli". Biochemical and Biophysical Research Communications. 203 (2): 798–804. doi:10.1006/bbrc.1994.2253. PMID   8093059.
  14. ↑ "File:Rooting-the-tree-of-life-by-transition-analyses-1745-6150-1-19-5.jpg - Wikipedia". commons.wikimedia.org. Retrieved 2023-05-02.
  15. ↑ Tatsuta T, Langer T (January 2008). "Quality control of mitochondria: protection against neurodegeneration and ageing". The EMBO Journal. 27 (2): 306–314. doi:10.1038/sj.emboj.7601972. PMC   2234350 . PMID   18216873.
  16. ↑ Kester JC, Kandror O, Akopian T, Chase MR, Zhu J, Rubin EJ, Goldberg AL, Fortune SM (January 2021). "ClpX Is Essential and Activated by Single-Strand DNA Binding Protein in Mycobacteria". Journal of Bacteriology. 203 (4). doi:10.1128/JB.00608-20. PMC   7847540 . PMID   33229461.
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