| CLPP | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | CLPP , PRLTS3, DFNB81, caseinolytic mitochondrial matrix peptidase proteolytic subunit | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 601119 MGI: 1858213 HomoloGene: 4385 GeneCards: CLPP | ||||||||||||||||||||||||||||||||||||||||||||||||||
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ATP-dependent Clp protease proteolytic subunit (ClpP) is an enzyme that in humans is encoded by the CLPP gene. [5] [6] This protein is an essential component to form the protein complex of Clp protease (Endopeptidase Clp).
Enzyme ClpP is a highly conserved serine protease present throughout bacteria and also found in the mitochondria and chloroplasts of eukaryotic cells. [7] [8] 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. [9]
Some bacteria have multiple ClpPs, like P. aeruginosa, which has two distinct ClpP isoforms ClpP1 and ClpP2. These isoforms have differences in assembly and functional characteristics. P. aeruginosa produces two forms of the ClpP peptidase, PaClpP114 and PaClpP17P27, which in complex with ClpX or ClpA form functional proteases. PaClpP2 is not able to form an active peptidase on its own but it needs PaClpP1 to be active. [10]
In bacteria, it was shown that ClpP is able 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. [11] In several bacteria, such as E. coli , proteins tagged with the SsrA peptide (ANDENYALAA) encoded by tmRNA are digested by Clp proteases. [12] Proteases target damaged or misfolded proteins, transcription factors and signaling proteins in bacteria to coordinate complex cell responses and thus they have robust importance for the physiology and virulence of bacteria. [13]
In P. aeruginosa, ClpP1 is expressed constitutively throughout growth whereas ClpP2 expression is induced 10-fold in stationary phase. Quorum-sensing transcription factor LasR activates expression of ClpP2 in stationary phase. ClpP1 and ClpP2 have differential cleavage specificities which contributes to total peptidase activity of PaClpP17P27. Peptidase and protease action of PaClpP17P27 produces cleavage products that enhance biofilm formation in P. aeruginosa. [10]
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. [6]
ClpP protease is a major contributor for mitochondrial protein quality control system and removing 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. [14]
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. [15]
ClpP has been shown to be over-expressed in the tumour cells of a subset of cancer patients. This can be exploited by therapeutic agents, including by the hyperactivation of ClpP to cause selective cancer cell lethality. [16]
Intracellular proteases have a role in bacterial virulence. Deletion of ClpP causes growth inhibition or loss of virulence in many bacterial species which makes them a good target for developing new antimicrobial agents. Currently there are no approved antimicrobial agents that target bacterial proteases. [17] PaClpP2 is required for proper biofilm development in opportunistic pathogen P. aeruginosa. Deletion of PaClpP2 or mutation of PaClpP2 active site notably decrease biofilm thickness of P. aeruginosa. This founding has relevance in development of new antimicrobial agents against P. aeruginosa. [10]
A protease is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do this by cleaving the peptide bonds within proteins by hydrolysis, a reaction where water breaks bonds. Proteases are involved in many biological functions, including digestion of ingested proteins, protein catabolism, and cell signaling.
GroEL is a protein which belongs to the chaperonin family of molecular chaperones, and is found in many bacteria. It is required for the proper folding of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein complex GroES. In eukaryotes the organellar proteins Hsp60 and Hsp10 are structurally and functionally nearly identical to GroEL and GroES, respectively, due to their endosymbiotic origin.
Virulence factors are cellular structures, molecules and regulatory systems that enable microbial pathogens to achieve the following:
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
In molecular biology, the Signal Peptide Peptidase (SPP) is a type of protein that specifically cleaves parts of other proteins. It is an intramembrane aspartyl protease with the conserved active site motifs 'YD' and 'GxGD' in adjacent transmembrane domains (TMDs). Its sequences is highly conserved in different vertebrate species. SPP cleaves remnant signal peptides left behind in membrane by the action of signal peptidase and also plays key roles in immune surveillance and the maturation of certain viral proteins.
The gene rpoS encodes the sigma factor sigma-38, a 37.8 kD protein in Escherichia coli. Sigma factors are proteins that regulate transcription in bacteria. Sigma factors can be activated in response to different environmental conditions. rpoS is transcribed in late exponential phase, and RpoS is the primary regulator of stationary phase genes. RpoS is a central regulator of the general stress response and operates in both a retroactive and a proactive manner: it not only allows the cell to survive environmental challenges, but it also prepares the cell for subsequent stresses (cross-protection). The transcriptional regulator CsgD is central to biofilm formation, controlling the expression of the curli structural and export proteins, and the diguanylate cyclase, adrA, which indirectly activates cellulose production. The rpoS gene most likely originated in the gammaproteobacteria.
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.
In enzymology, arginine kinase is an enzyme that catalyzes the chemical reaction
Lon protease homolog, mitochondrial is a protease, an enzyme that in humans is encoded by the LONP1 gene.
Mitochondrial-processing peptidase subunit beta is an enzyme that in humans is encoded by the PMPCB gene. This gene is a member of the peptidase M16 family and encodes a protein with a zinc-binding motif. This protein is located in the mitochondrial matrix and catalyzes the cleavage of the leader peptides of precursor proteins newly imported into the mitochondria, though it only functions as part of a heterodimeric complex.
Mitochondrial-processing peptidase subunit alpha is an enzyme that in humans is encoded by the PMPCA gene. This gene PMPCA encoded a protein that is a member of the peptidase M16 family. This protein is located in the mitochondrial matrix and catalyzes the cleavage of the leader peptides of precursor proteins newly imported into the mitochondria, though it only functions as part of a heterodimeric complex.
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).
The N-end rule is a rule that governs the rate of protein degradation through recognition of the N-terminal residue of proteins. The rule states that the N-terminal amino acid of a protein determines its half-life. The rule applies to both eukaryotic and prokaryotic organisms, but with different strength, rules, and outcome. In eukaryotic cells, these N-terminal residues are recognized and targeted by ubiquitin ligases, mediating ubiquitination thereby marking the protein for degradation. The rule was initially discovered by Alexander Varshavsky and co-workers in 1986. However, only rough estimations of protein half-life can be deduced from this 'rule', as N-terminal amino acid modification can lead to variability and anomalies, whilst amino acid impact can also change from organism to organism. Other degradation signals, known as degrons, can also be found in sequence.
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.
In molecular biology, the Lon protease family is a family of enzymes that break peptide bonds in proteins resulting in smaller peptides or amino acids. They are found in archaea, bacteria and eukaryotes. Lon proteases are ATP-dependent serine peptidases belonging to the MEROPS peptidase family S16. In the eukaryotes the majority of the Lon proteases are located in the mitochondrial matrix. In yeast, the Lon protease PIM1 is located in the mitochondrial matrix. It is required for mitochondrial function, it is constitutively expressed but is increased after thermal stress, suggesting that PIM1 may play a role in the heat shock response. Lon proteases have two specific subfamilies: LonA and LonB, differentiated by the number of AAA+ domains found in the protein.
Mitochondrial processing peptidase is an enzyme complex found in mitochondria which cleaves signal sequences from mitochondrial proteins. In humans this complex is composed of two subunits encoded by the genes PMPCA, and PMPCB. The enzyme is also known as. This enzyme catalyses the following chemical reaction
Acyldepsipeptide or cyclic acyldepsipeptide (ADEP) is a class of potential antibiotics first isolated from bacteria and act by deregulating the ClpP protease. Natural ADEPs were originally found as products of aerobic fermentation in Streptomyces hawaiiensis, A54556A and B, and in the culture broth of Streptomyces species, enopeptin A and B. ADEPs are of great interest in drug development due to their antibiotic properties and thus are being modified in attempt to achieve greater antimicrobial activity.
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 and is to form the protein complex of Clp protease.
The Curli protein is a type of amyloid fiber produced by certain strains of enterobacteria. They are extracellular fibers located on bacteria such as E. coli and Salmonella spp. These fibers serve to promote cell community behavior through biofilm formation in the extracellular matrix. Amyloids are associated with several human neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, and prion diseases. The study of curli may help to understand human diseases thought to arise from improper amyloid fiber formation. The curli pili are generally assembled through the extracellular nucleation/precipitation pathway.
A. C. Matin is an Indian-American microbiologist, immunologist, academician and researcher. He is a professor of microbiology and immunology at Stanford University School of Medicine.
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