Biology:CLPB

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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,[1][2][3] 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.[4][5] It is a potent protein disaggregase that chaperones the mitochondrial intermembrane space.[6] 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.[4][7] Recently, heterozygous, dominant negative mutations in CLPB have been identified as a cause of severe congenital neutropenia (SCN).[8]

Structure

Gene

The CLPB gene has 19 exons and is located at the chromosome band 11q13.4.[3]

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).[6] After processing, the mature mitochondrial protein has a theoretical pI of 7.53.[9] Skd3 is further processed by the mitochondrial rhomboid protease PARL at amino acid 127.[6][10] 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.[11] The domain composition of human Skd3 is different from that of microbial or plant orthologs.[6][12] Notably, the presence of ankyrin repeats replaced the first of two ATPase domains found in bacteria and fungi.[13][14]

Function

Skd3 belongs to the HCLR clade of the large AAA+ superfamily.[6][15] 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.[16][17] Skd3 does not cooperate with HSP70, unlike its bacterial orthologue.[6] The in vitro ATPase activity of Skd3 has been confirmed.[4][6][18] Skd3 is a potent disaggregase in vitro and is activated by PARL to increase disaggregation activity by over 10-fold.[6] Indeed, PARL-activated Skd3 is capable of disassembling alpha-synuclein fibrils in vitro.[6] Even though the bacterial orthologue, ClpB, contributes to the thermotolerance of cells, it is yet unclear if Skd3 plays a similar role within mitochondria.[16][19] The interaction with protein like HAX1 suggests that human Skd3 may be involved in apoptosis.[4] 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.[6][20] 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.[13][14] Either the ankyrin repeats alone or the AAA+ domain were found to be insufficient to support disaggregation activity.[6] 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.[21][22][23] />

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.[16] 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][7][24] Further investigation into Skd3 may shed a new light on the diagnosis of this disease.

Interactions

This protein is known to interact with:

References

  1. ↑ "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. March 2001. doi:10.1101/gr.GR1547R. PMID 11230166. 
  2. ↑ "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. January 1995. doi:10.1016/0378-1119(94)00697-Q. PMID 7835694. 
  3. ↑ 3.0 3.1 "Entrez Gene: CLPB ClpB caseinolytic peptidase B homolog (E. coli)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=81570. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "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. February 2015. doi:10.1016/j.ajhg.2014.12.013. PMID 25597510. 
  5. ↑ "CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria". American Journal of Human Genetics 96 (2): 258–65. February 2015. doi:10.1016/j.ajhg.2014.12.020. PMID 25597511. 
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 6.15 6.16 6.17 6.18 6.19 6.20 6.21 6.22 6.23 6.24 6.25 6.26 6.27 6.28 6.29 6.30 6.31 6.32 6.33 6.34 6.35 Cupo, Ryan R; Shorter, James (2020-06-23). Berger, James M. ed. "Skd3 (human CLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations". eLife 9: e55279. doi:10.7554/eLife.55279. ISSN 2050-084X. PMID 32573439. 
  7. ↑ 7.0 7.1 "Novel CLPB mutation in a patient with 3-methylglutaconic aciduria causing severe neurological involvement and congenital neutropenia". Clinical Immunology 165: 1–3. April 2016. doi:10.1016/j.clim.2016.02.008. PMID 26916670. 
  8. ↑ Warren, Julia T; Cupo, Ryan R; Wattanasirakul, Peeradol; Spencer, David; Locke, Adam E; Makaryan, Vahagn; Bolyard, Audrey Anna; Kelley, Meredith L et al. (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. PMID 34115842. PMC 8814677. https://doi.org/10.1182/blood.2021010762. 
  9. ↑ "Q9H078 - CLPB_HUMAN". Uniprot. https://www.uniprot.org/uniprot/Q9H078. 
  10. ↑ 10.0 10.1 Saita, Shotaro; Nolte, Hendrik; Fiedler, Kai Uwe; Kashkar, Hamid; Venne, A. Saskia; Zahedi, René P.; Krüger, Marcus; Langer, Thomas (April 2017). "PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis" (in en). Nature Cell Biology 19 (4): 318–328. doi:10.1038/ncb3488. ISSN 1476-4679. PMID 28288130. https://www.nature.com/articles/ncb3488. 
  11. ↑ "A camel passes through the eye of a needle: protein unfolding activity of Clp ATPases". Molecular Microbiology 61 (5): 1094–100. September 2006. doi:10.1111/j.1365-2958.2006.05309.x. PMID 16879409. 
  12. ↑ 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" (in en). PLOS ONE 10 (2): e0117192. doi:10.1371/journal.pone.0117192. ISSN 1932-6203. PMID 25710177. Bibcode: 2015PLoSO..1017192E. 
  13. ↑ 13.0 13.1 "The ankyrin repeat as molecular architecture for protein recognition". Protein Science 13 (6): 1435–48. June 2004. doi:10.1110/ps.03554604. PMID 15152081. 
  14. ↑ 14.0 14.1 "Ankyrin repeat: a unique motif mediating protein-protein interactions". Biochemistry 45 (51): 15168–78. December 2006. doi:10.1021/bi062188q. PMID 17176038. 
  15. ↑ 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. 
  16. ↑ 16.0 16.1 16.2 "Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria". Journal of Medical Genetics 52 (5): 303–11. May 2015. doi:10.1136/jmedgenet-2014-102952. PMID 25650066. 
  17. ↑ "The AAA+ superfamily of functionally diverse proteins". Genome Biology 9 (4): 216. 30 April 2008. doi:10.1186/gb-2008-9-4-216. PMID 18466635. 
  18. ↑ Mróz, Dagmara; Wyszkowski, Hubert; Szablewski, Tomasz; Zawieracz, Katarzyna; Dutkiewicz, Rafał; Bury, Katarzyna; Wortmann, Saskia B.; Wevers, Ron A. et al. (April 2020). "CLPB (caseinolytic peptidase B homolog), the first mitochondrial protein refoldase associated with human disease" (in en). Biochimica et Biophysica Acta (BBA) - General Subjects 1864 (4): 129512. doi:10.1016/j.bbagen.2020.129512. PMID 31917998. 
  19. ↑ "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. October 1998. doi:10.1128/JB.180.19.5165-5172.1998. PMID 9748451. 
  20. ↑ 20.0 20.1 20.2 Chen, Xufeng; Glytsou, Christina; Zhou, Hua; Narang, Sonali; Reyna, Denis E.; Lopez, Andrea; Sakellaropoulos, Theodore; Gong, Yixiao et al. (July 2019). "Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment" (in en). Cancer Discovery 9 (7): 890–909. doi:10.1158/2159-8290.CD-19-0117. ISSN 2159-8274. PMID 31048321. 
  21. ↑ "Chaperoned protein disaggregation--the ClpB ring uses its central channel". Cell 119 (5): 579–81. November 2004. doi:10.1016/j.cell.2004.11.018. PMID 15550237. 
  22. ↑ "Thermotolerance requires refolding of aggregated proteins by substrate translocation through the central pore of ClpB". Cell 119 (5): 653–65. November 2004. doi:10.1016/j.cell.2004.11.027. PMID 15550247. 
  23. ↑ "ClpB chaperone passively threads soluble denatured proteins through its central pore". Genes to Cells 19 (12): 891–900. December 2014. doi:10.1111/gtc.12188. PMID 25288401. 
  24. ↑ "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. 12 June 2016. doi:10.1186/s12967-016-0930-9. PMID 27290639. 
  25. ↑ 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" (in en). iScience 19: 1065–1078. doi:10.1016/j.isci.2019.08.056. ISSN 2589-0042. PMID 31522117. Bibcode: 2019iSci...19.1065Y. 

External links

Further reading



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