Caseinolytic peptidase B protein homolog(CLPB), also known as mitochondrial AAA ATPase chaperonin, is an enzyme that in humans is encoded by the CLPBgene,[1][2][3] which encodes an ATP-dependent protease and chaperone. CLPB is localized in mitochondria and widely expressed in human tissues. High expression in adult brain and low expression in granulocyte is found.[4][5] It is a chaperone involved in disaggregating proteins and also has a role in de novoprotein synthesis under mild stress conditions. Mutations in "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.[4][6]
The CLPB gene has 19 exons and is located at the chromosome band 11q13.4.[3]
Protein
CLPB has five isoforms due to alternative splicing. Isoform 1 is considered to have the 'canonical' sequence. The protein is 78.7 kDa in size and composed of 707 amino acids. It contains an N-terminal mitochondrial targeting sequence (1-36 amino acids). After processing, the mature mitochondrial protein has a theoretical pI of 8.53.[7] CLPB has a specific C-terminal D2 domain and proteins with this domain form the sub-family of Caseinolytic peptidase (Clp) proteins, also called HSP100.[8] The domain composition of human CLPB is different from that of microbial or plant orthologs. Notably, the presence of ankyrin repeats replaced the first of two ATPase domains found in bacteria and fungi.[9][10]
Function
CLPB belongs to the large AAA+ superfamily. The unifying characteristic of this family is the hydrolysis of ATP through the AAA+ domain to produce energy required to catalyze protein unfolding, disassembly and disaggregation.[11][12] CLPB cooperates with HSP70 and its in vivo ATPase activity has been confirmed. This protein contributes to the thermotolerance of cells and appears to be required for mitochondrial function by acting as a protein chaperone.[11][13] The interaction with protein like HAX1 suggests that human CLPB may be involved in apoptosis.[4] In humans, the presence of ankyrin repeats replaced the first of two ATPase domains found in bacteria and fungi, which might have evolved to ensure more elaborate substrate recognition or to support a putative chaperone function.[9][10] With only one ATPase domain, CLPB is postulated competent in the use of ATP hydrolysis energy for threading unfolded polypeptide through the central channel of the hexamer ring.[14][15][16]
Clinical significance
Neonatal encephalopathy is a kind of severe neurological impairment in the newborn with no specific clinical sign at the early stage of life, and its diagnosis remains a challenge. This neonatal encephalopathy includes a heterogeneous group of 3- methylgutaconic aciduria syndromes and loss of CLPB function is reported to be one of the causes. Knocking down "CLPB" gene in the zebrafish induced reduction of growth and increment of motor activity, which is similar to the signs observed in patients.[11] Its loss may lead to a broad phenotypic spectrum encompassing intellectual disability/developmental delay, congenital neutropenia, progressive brain atrophy, movement disorder, and bilateral cataracts, with 3-methylglutaconic aciduria.[4][6][17] Further investigation into CLPB may shed a new light on the diagnosis of this disease.
↑Périer F, Radeke CM, Raab-Graham KF, Vandenberg CA (January 1995). "Expression of a putative ATPase suppresses the growth defect of a yeast potassium transport mutant: identification of a mammalian member of the Clp/HSP104 family". Gene. 152 (2): 157–63. doi:10.1016/0378-1119(94)00697-Q. PMID7835694.
↑ 6.06.1Kiykim A, Garncarz W, Karakoc-Aydiner E, Ozen A, Kiykim E, Yesil G, Boztug K, Baris S (April 2016). "Novel CLPB mutation in a patient with 3-methylglutaconic aciduria causing severe neurological involvement and congenital neutropenia". Clinical Immunology. 165: 1–3. doi:10.1016/j.clim.2016.02.008. PMID26916670.
↑Weibezahn J, Tessarz P, Schlieker C, Zahn R, Maglica Z, Lee S, Zentgraf H, Weber-Ban EU, Dougan DA, Tsai FT, Mogk A, Bukau B (November 2004). "Thermotolerance requires refolding of aggregated proteins by substrate translocation through the central pore of ClpB". Cell. 119 (5): 653–65. doi:10.1016/j.cell.2004.11.027. PMID15550247.
↑Nakazaki Y, Watanabe YH (December 2014). "ClpB chaperone passively threads soluble denatured proteins through its central pore". Genes to Cells. 19 (12): 891–900. doi:10.1111/gtc.12188. PMID25288401.
Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID16189514.
Leonard D, Ajuh P, Lamond AI, Legerski RJ (September 2003). "hLodestar/HuF2 interacts with CDC5L and is involved in pre-mRNA splicing". Biochemical and Biophysical Research Communications. 308 (4): 793–801. doi:10.1016/S0006-291X(03)01486-4. PMID12927788.