CLPB

Last updated
CLPB
Identifiers
Aliases CLPB , HSP78, SKD3, ANKCLB, MEGCANN, MGCA7, ClpB homolog, mitochondrial AAA ATPase chaperonin, caseinolytic mitochondrial matrix peptidase chaperone subunit B, SCN9, MGCA7A
External IDs OMIM: 616254 MGI: 1100517 HomoloGene: 32067 GeneCards: CLPB
Orthologs
SpeciesHumanMouse
Entrez

81570

20480

Ensembl

ENSG00000162129

ENSMUSG00000001829

UniProt

Q9H078

Q60649

RefSeq (mRNA)

NM_001258392
NM_001258393
NM_001258394
NM_030813

NM_009191
NM_001363991

RefSeq (protein)

NP_001245321
NP_001245322
NP_001245323
NP_110440

NP_033217
NP_001350920

Location (UCSC) Chr 11: 72.29 – 72.43 Mb Chr 7: 101.31 – 101.44 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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, [5] [6] [7] 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. [8] [9] It is a potent protein disaggregase that chaperones the mitochondrial intermembrane space. [10] 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. [8] [11] Recently, heterozygous, dominant negative mutations in CLPB have been identified as a cause of severe congenital neutropenia (SCN). [12]

Contents

Structure

Gene

The CLPB gene has 19 exons and is located at the chromosome band 11q13.4. [7]

Protein

Skd3 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 (1-92 amino acids). [10] After processing, the mature mitochondrial protein has a theoretical pI of 7.53. [13] Skd3 is further processed by the mitochondrial rhomboid protease PARL at amino acid 127. [10] [14] Skd3 has a specific C-terminal D2 domain and proteins with this domain form the sub-family of Caseinolytic peptidase (Clp) proteins, also called HSP100. [15] The domain composition of human Skd3 is different from that of microbial or plant orthologs. [10] [16] Notably, the presence of ankyrin repeats replaced the first of two ATPase domains found in bacteria and fungi. [17] [18]

Function

Skd3 belongs to the HCLR clade of the large AAA+ superfamily. [10] [19] 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. [20] [21] Skd3 does not cooperate with HSP70, unlike its bacterial orthologue. [10] The in vitro ATPase activity of Skd3 has been confirmed. [8] [10] [22] Skd3 is a potent disaggregase in vitro and is activated by PARL to increase disaggregation activity by over 10-fold. [10] Indeed, PARL-activated Skd3 is capable of disassembling alpha-synuclein fibrils in vitro. [10] Even though the bacterial orthologue, ClpB, contributes to the thermotolerance of cells, it is yet unclear if Skd3 plays a similar role within mitochondria. [20] [23] The interaction with protein like HAX1 suggests that human Skd3 may be involved in apoptosis. [8] Indeed, Skd3 solubilizes HAX1 in cells and the deletion of the CLPB gene in human cells has been shown to sensitize cells to apoptotic signals. [10] [24] 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. [17] [18] Either the ankyrin repeats alone or the AAA+ domain were found to be insufficient to support disaggregation activity. [10] With only one ATPase domain, Skd3 is postulated competent in the use of ATP hydrolysis energy for threading unfolded polypeptide through the central channel of the hexamer ring. [25] [26] [27] />

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-methylglutaconic aciduria syndromes and loss of Skd3 function is reported to be one of the causes. Knocking down the clpB gene in the zebrafish induced reduction of growth and increment of motor activity, which is similar to the signs observed in patients. [20] 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. [8] [11] [28] Further investigation into Skd3 may shed a new light on the diagnosis of this disease.

Interactions

This protein is known to interact with:

Related Research Articles

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References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000162129 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000001829 - 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. ↑ Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A (March 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC   311072 . PMID   11230166.
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  7. 1 2 "Entrez Gene: CLPB ClpB caseinolytic peptidase B homolog (E. coli)".
  8. 1 2 3 4 5 6 Wortmann SB, Ziętkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, et al. (February 2015). "CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder". American Journal of Human Genetics. 96 (2): 245–57. doi:10.1016/j.ajhg.2014.12.013. PMC   4320260 . PMID   25597510.
  9. ↑ Saunders C, Smith L, Wibrand F, Ravn K, Bross P, Thiffault I, Christensen M, Atherton A, Farrow E, Miller N, Kingsmore SF, Ostergaard E (February 2015). "CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria". American Journal of Human Genetics. 96 (2): 258–65. doi:10.1016/j.ajhg.2014.12.020. PMC   4320254 . PMID   25597511.
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  12. ↑ Warren, Julia T; Cupo, Ryan R; Wattanasirakul, Peeradol; Spencer, David; Locke, Adam E; Makaryan, Vahagn; Bolyard, Audrey Anna; Kelley, Meredith L; Kingston, Natalie L; Shorter, James; Bellanné-Chantelot, Christine (2021-06-11). "Heterozygous Variants of CLPB are a Cause of Severe Congenital Neutropenia". Blood. 139 (blood.2021010762): 779–791. doi:10.1182/blood.2021010762. ISSN   0006-4971. PMC   8814677 . PMID   34115842.
  13. ↑ "Q9H078 - CLPB_HUMAN". Uniprot.
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  15. ↑ Zolkiewski M (September 2006). "A camel passes through the eye of a needle: protein unfolding activity of Clp ATPases". Molecular Microbiology. 61 (5): 1094–100. doi:10.1111/j.1365-2958.2006.05309.x. PMC   1852505 . PMID   16879409.
  16. ↑ Erives, Albert J.; Fassler, Jan S. (2015-02-24). "Metabolic and Chaperone Gene Loss Marks the Origin of Animals: Evidence for Hsp104 and Hsp78 Chaperones Sharing Mitochondrial Enzymes as Clients". PLOS ONE. 10 (2): e0117192. Bibcode:2015PLoSO..1017192E. doi: 10.1371/journal.pone.0117192 . ISSN   1932-6203. PMC   4339202 . PMID   25710177.
  17. 1 2 Mosavi LK, Cammett TJ, Desrosiers DC, Peng ZY (June 2004). "The ankyrin repeat as molecular architecture for protein recognition". Protein Science. 13 (6): 1435–48. doi:10.1110/ps.03554604. PMC   2279977 . PMID   15152081.
  18. 1 2 Li J, Mahajan A, Tsai MD (December 2006). "Ankyrin repeat: a unique motif mediating protein-protein interactions". Biochemistry. 45 (51): 15168–78. CiteSeerX   10.1.1.502.2771 . doi:10.1021/bi062188q. PMID   17176038.
  19. ↑ Erzberger, Jan P.; Berger, James M. (2006-05-11). "Evolutionary relationships and structural mechanisms of aaa+ proteins". Annual Review of Biophysics and Biomolecular Structure. 35 (1): 93–114. doi:10.1146/annurev.biophys.35.040405.101933. ISSN   1056-8700. PMID   16689629.
  20. 1 2 3 Capo-Chichi JM, Boissel S, Brustein E, Pickles S, Fallet-Bianco C, Nassif C, Patry L, Dobrzeniecka S, Liao M, Labuda D, Samuels ME, Hamdan FF, Vande Velde C, Rouleau GA, Drapeau P, Michaud JL (May 2015). "Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria". Journal of Medical Genetics. 52 (5): 303–11. doi:10.1136/jmedgenet-2014-102952. PMID   25650066. S2CID   36062854.
  21. ↑ Snider J, Thibault G, Houry WA (30 April 2008). "The AAA+ superfamily of functionally diverse proteins". Genome Biology. 9 (4): 216. doi: 10.1186/gb-2008-9-4-216 . PMC   2643927 . PMID   18466635.
  22. ↑ Mróz, Dagmara; Wyszkowski, Hubert; Szablewski, Tomasz; Zawieracz, Katarzyna; Dutkiewicz, Rafał; Bury, Katarzyna; Wortmann, Saskia B.; Wevers, Ron A.; Ziętkiewicz, Szymon (April 2020). "CLPB (caseinolytic peptidase B homolog), the first mitochondrial protein refoldase associated with human disease". Biochimica et Biophysica Acta (BBA) - General Subjects. 1864 (4): 129512. doi: 10.1016/j.bbagen.2020.129512 . hdl: 2066/219662 . PMID   31917998.
  23. ↑ Thomas JG, Baneyx F (October 1998). "Roles of the Escherichia coli small heat shock proteins IbpA and IbpB in thermal stress management: comparison with ClpA, ClpB, and HtpG In vivo". Journal of Bacteriology. 180 (19): 5165–72. doi:10.1128/JB.180.19.5165-5172.1998. PMC   107554 . PMID   9748451.
  24. 1 2 3 Chen, Xufeng; Glytsou, Christina; Zhou, Hua; Narang, Sonali; Reyna, Denis E.; Lopez, Andrea; Sakellaropoulos, Theodore; Gong, Yixiao; Kloetgen, Andreas; Yap, Yoon Sing; Wang, Eric (July 2019). "Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment". Cancer Discovery. 9 (7): 890–909. doi:10.1158/2159-8290.CD-19-0117. ISSN   2159-8274. PMC   6606342 . PMID   31048321.
  25. ↑ Horwich AL (November 2004). "Chaperoned protein disaggregation--the ClpB ring uses its central channel". Cell. 119 (5): 579–81. doi: 10.1016/j.cell.2004.11.018 . PMID   15550237.
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  27. ↑ 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 . PMID   25288401. S2CID   7170147.
  28. ↑ Pronicka E, Piekutowska-Abramczuk D, Ciara E, Trubicka J, Rokicki D, Karkucińska-Więckowska A, Pajdowska M, Jurkiewicz E, Halat P, Kosińska J, Pollak A, Rydzanicz M, Stawinski P, Pronicki M, Krajewska-Walasek M, Płoski R (12 June 2016). "New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre". Journal of Translational Medicine. 14 (1): 174. doi: 10.1186/s12967-016-0930-9 . PMC   4903158 . PMID   27290639.
  29. ↑ Yoshinaka, Takahiro; Kosako, Hidetaka; Yoshizumi, Takuma; Furukawa, Ryo; Hirano, Yu; Kuge, Osamu; Tamada, Taro; Koshiba, Takumi (2019-09-27). "Structural Basis of Mitochondrial Scaffolds by Prohibitin Complexes: Insight into a Role of the Coiled-Coil Region". iScience. 19: 1065–1078. Bibcode:2019iSci...19.1065Y. doi:10.1016/j.isci.2019.08.056. ISSN   2589-0042. PMC   6745515 . PMID   31522117.

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