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]

Quick Facts Identifiers, Aliases ...

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; OMA:CLPB - orthologs
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q13.4 Start 72,285,495 bp[1] End 72,434,680 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 E2 Start 101,312,840 bp[2] End 101,444,713 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sperm right adrenal gland islet of Langerhans right lobe of liver stromal cell of endometrium left adrenal gland monocyte sural nerve gastrocnemius muscle prefrontal cortex Top expressed in spermatid seminiferous tubule spermatocyte otic placode saccule myocardium of ventricle brown adipose tissue right ventricle proximal tubule soleus muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding ATPase activity protein binding hydrolase activity ATP binding molecular function Cellular component mitochondrion cellular component Biological process cellular response to heat Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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
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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] />

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.

This protein is known to interact with:

• HAX1^[8][10][24]
• PARL^[10][14]
• HTRA2^[10]
• SMAC/DIABLO^[10]
• OPA1^[10]
• OPA3^[24]
• PHB2^[10][29]
• MICU1^[10]
• MICU2^[10]
• SLC25A25^[10]
• SLC25A13^[10]
• TIMM8A^[10]
• TIMM8B^[10]
• TIMM13^[10]
• TIMM21^[10]
• TIMM22^[10]
• TIMM23^[10]
• TIMM50^[10]
• NDUFA8^[10]
• NDUFA11^[10]
• NDUFA13^[10]
• NDUFB7^[10]
• NDUFB10^[10]
• TTC19^[10]
• COX11^[10]
• CYC1^[10]