{{Short description|Protein found in humans}} {{Infobox_gene}} '''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'',<ref name="pmid11230166">{{cite journal | vauthors = 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 | title = Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs | journal = Genome Research | volume = 11 | issue = 3 | pages = 422–35 | date = March 2001 | pmid = 11230166 | pmc = 311072 | doi = 10.1101/gr.GR1547R }}</ref><ref name="pmid7835694">{{cite journal | vauthors = Périer F, Radeke CM, Raab-Graham KF, Vandenberg CA | title = 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 | journal = Gene | volume = 152 | issue = 2 | pages = 157–63 | date = January 1995 | pmid = 7835694 | doi = 10.1016/0378-1119(94)00697-Q }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: CLPB ClpB caseinolytic peptidase B homolog (E. coli)| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=81570}}</ref> 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.<ref name="pmid25597510">{{cite journal | vauthors = Wortmann SB, Ziętkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lücke T, Õunap K, Zordania R, Yaplito-Lee J, van Bokhoven H, Spelbrink JN, Vaz FM, Pras-Raves M, Ploski R, Pronicka E, Klein C, Willemsen MA, de Brouwer AP, Prokisch H, Katsanis N, Wevers RA | display-authors = 6 | title = CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder | journal = American Journal of Human Genetics | volume = 96 | issue = 2 | pages = 245–57 | date = February 2015 | pmid = 25597510 | doi = 10.1016/j.ajhg.2014.12.013 | pmc=4320260}}</ref><ref name="pmid25597511">{{cite journal | vauthors = Saunders C, Smith L, Wibrand F, Ravn K, Bross P, Thiffault I, Christensen M, Atherton A, Farrow E, Miller N, Kingsmore SF, Ostergaard E | title = CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria | journal = American Journal of Human Genetics | volume = 96 | issue = 2 | pages = 258–65 | date = February 2015 | pmid = 25597511 | doi = 10.1016/j.ajhg.2014.12.020 | pmc=4320254}}</ref> It is a potent protein disaggregase that chaperones the mitochondrial intermembrane space.<ref name=":0">{{Cite journal|last1=Cupo|first1=Ryan R|last2=Shorter|first2=James|date=2020-06-23|editor-last=Berger|editor-first=James M|title=Skd3 (human CLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations|journal=eLife|volume=9|article-number=e55279|doi=10.7554/eLife.55279|pmid=32573439|pmc=7343390|issn=2050-084X|doi-access=free}}</ref> 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.<ref name="pmid25597510"/><ref name="pmid26916670">{{cite journal | vauthors = Kiykim A, Garncarz W, Karakoc-Aydiner E, Ozen A, Kiykim E, Yesil G, Boztug K, Baris S | title = Novel CLPB mutation in a patient with 3-methylglutaconic aciduria causing severe neurological involvement and congenital neutropenia | journal = Clinical Immunology | volume = 165 | pages = 1–3 | date = April 2016 | pmid = 26916670 | doi = 10.1016/j.clim.2016.02.008 }}</ref> Recently, heterozygous, dominant negative mutations in ''CLPB'' have been identified as a cause of severe congenital neutropenia (SCN).<ref>{{Cite journal|last1=Warren|first1=Julia T|last2=Cupo|first2=Ryan R|last3=Wattanasirakul|first3=Peeradol|last4=Spencer|first4=David|last5=Locke|first5=Adam E|last6=Makaryan|first6=Vahagn|last7=Bolyard|first7=Audrey Anna|last8=Kelley|first8=Meredith L|last9=Kingston|first9=Natalie L|last10=Shorter|first10=James|last11=Bellanné-Chantelot|first11=Christine|date=2021-06-11|title=Heterozygous Variants of CLPB are a Cause of Severe Congenital Neutropenia|journal=Blood|volume=139 |issue=blood.2021010762|pages=779–791 |doi=10.1182/blood.2021010762|pmid=34115842|pmc=8814677 |issn=0006-4971}}</ref>
== Structure ==
=== Gene ===
The ''CLPB'' gene has 19 exons and is located at the chromosome band 11q13.4.<ref name="entrez" />
=== 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).<ref name=":0" /> After processing, the mature mitochondrial protein has a theoretical pI of 7.53.<ref>{{cite web | url = https://www.uniprot.org/uniprot/Q9H078| work = Uniprot | title = Q9H078 - CLPB_HUMAN}}</ref> Skd3 is further processed by the mitochondrial rhomboid protease PARL at amino acid 127.<ref name=":0" /><ref name=":1">{{Cite journal|last1=Saita|first1=Shotaro|last2=Nolte|first2=Hendrik|last3=Fiedler|first3=Kai Uwe|last4=Kashkar|first4=Hamid|last5=Venne|first5=A. Saskia|last6=Zahedi|first6=René P.|last7=Krüger|first7=Marcus|last8=Langer|first8=Thomas|date=April 2017|title=PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis|url=https://www.nature.com/articles/ncb3488|journal=Nature Cell Biology|language=en|volume=19|issue=4|pages=318–328|doi=10.1038/ncb3488|pmid=28288130|s2cid=3744933|issn=1476-4679|url-access=subscription}}</ref> 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.<ref name="pmid16879409">{{cite journal | vauthors = Zolkiewski M | title = A camel passes through the eye of a needle: protein unfolding activity of Clp ATPases | journal = Molecular Microbiology | volume = 61 | issue = 5 | pages = 1094–100 | date = September 2006 | pmid = 16879409 | doi = 10.1111/j.1365-2958.2006.05309.x | pmc=1852505}}</ref> The domain composition of human Skd3 is different from that of microbial or plant orthologs.<ref name=":0" /><ref>{{Cite journal|last1=Erives|first1=Albert J.|last2=Fassler|first2=Jan S.|date=2015-02-24|title=Metabolic and Chaperone Gene Loss Marks the Origin of Animals: Evidence for Hsp104 and Hsp78 Chaperones Sharing Mitochondrial Enzymes as Clients|journal=PLOS ONE|language=en|volume=10|issue=2|article-number=e0117192|doi=10.1371/journal.pone.0117192|issn=1932-6203|pmc=4339202|pmid=25710177|bibcode=2015PLoSO..1017192E|doi-access=free}}</ref> Notably, the presence of ankyrin repeats replaced the first of two ATPase domains found in bacteria and fungi.<ref name="pmid15152081">{{cite journal | vauthors = Mosavi LK, Cammett TJ, Desrosiers DC, Peng ZY | title = The ankyrin repeat as molecular architecture for protein recognition | journal = Protein Science | volume = 13 | issue = 6 | pages = 1435–48 | date = June 2004 | pmid = 15152081 | doi = 10.1110/ps.03554604 | pmc=2279977}}</ref><ref name="pmid17176038">{{cite journal | vauthors = Li J, Mahajan A, Tsai MD | title = Ankyrin repeat: a unique motif mediating protein-protein interactions | journal = Biochemistry | volume = 45 | issue = 51 | pages = 15168–78 | date = December 2006 | pmid = 17176038 | doi = 10.1021/bi062188q | citeseerx = 10.1.1.502.2771 }}</ref>
== Function ==
Skd3 belongs to the HCLR clade of the large AAA+ superfamily.<ref name=":0" /><ref>{{Cite journal|last1=Erzberger|first1=Jan P.|last2=Berger|first2=James M.|date=2006-05-11|title=Evolutionary relationships and structural mechanisms of aaa+ proteins|journal=Annual Review of Biophysics and Biomolecular Structure|volume=35|issue=1|pages=93–114|doi=10.1146/annurev.biophys.35.040405.101933|pmid=16689629|issn=1056-8700}}</ref> 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.<ref name="pmid25650066">{{cite journal | vauthors = 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 | title = Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria | journal = Journal of Medical Genetics | volume = 52 | issue = 5 | pages = 303–11 | date = May 2015 | pmid = 25650066 | doi = 10.1136/jmedgenet-2014-102952 | s2cid = 36062854 }}</ref><ref name="pmid18466635">{{cite journal | vauthors = Snider J, Thibault G, Houry WA | title = The AAA+ superfamily of functionally diverse proteins | journal = Genome Biology | volume = 9 | issue = 4 | page = 216 | date = 30 April 2008 | pmid = 18466635 | doi = 10.1186/gb-2008-9-4-216 | pmc=2643927 | doi-access = free }}</ref> Skd3 does not cooperate with HSP70, unlike its bacterial orthologue.<ref name=":0" /> The ''in vitro'' ATPase activity of Skd3 has been confirmed.<ref name="pmid25597510" /><ref name=":0" /><ref>{{Cite journal|last1=Mróz|first1=Dagmara|last2=Wyszkowski|first2=Hubert|last3=Szablewski|first3=Tomasz|last4=Zawieracz|first4=Katarzyna|last5=Dutkiewicz|first5=Rafał|last6=Bury|first6=Katarzyna|last7=Wortmann|first7=Saskia B.|last8=Wevers|first8=Ron A.|last9=Ziętkiewicz|first9=Szymon|date=April 2020|title=CLPB (caseinolytic peptidase B homolog), the first mitochondrial protein refoldase associated with human disease|journal=Biochimica et Biophysica Acta (BBA) - General Subjects|language=en|volume=1864|issue=4|article-number=129512|doi=10.1016/j.bbagen.2020.129512|pmid=31917998|doi-access=free|hdl=2066/219662|hdl-access=free}}</ref> Skd3 is a potent disaggregase ''in vitro'' and is activated by PARL to increase disaggregation activity by over 10-fold.<ref name=":0" /> Indeed, PARL-activated Skd3 is capable of disassembling alpha-synuclein fibrils ''in vitro''.<ref name=":0" /> Even though the bacterial orthologue, ClpB, contributes to the thermotolerance of cells, it is yet unclear if Skd3 plays a similar role within mitochondria.<ref name="pmid25650066"/><ref name="pmid9748451">{{cite journal | vauthors = Thomas JG, Baneyx F | title = 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 = Journal of Bacteriology | volume = 180 | issue = 19 | pages = 5165–72 | date = October 1998 | doi = 10.1128/JB.180.19.5165-5172.1998 | pmid = 9748451 | pmc=107554}}</ref> The interaction with protein like HAX1 suggests that human Skd3 may be involved in apoptosis.<ref name="pmid25597510"/> 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.<ref name=":0" /><ref name=":2">{{Cite journal|last1=Chen|first1=Xufeng|last2=Glytsou|first2=Christina|last3=Zhou|first3=Hua|last4=Narang|first4=Sonali|last5=Reyna|first5=Denis E.|last6=Lopez|first6=Andrea|last7=Sakellaropoulos|first7=Theodore|last8=Gong|first8=Yixiao|last9=Kloetgen|first9=Andreas|last10=Yap|first10=Yoon Sing|last11=Wang|first11=Eric|date=July 2019|title=Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment|journal=Cancer Discovery|language=en|volume=9|issue=7|pages=890–909|doi=10.1158/2159-8290.CD-19-0117|issn=2159-8274|pmc=6606342|pmid=31048321}}</ref> 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.<ref name="pmid15152081"/><ref name="pmid17176038"/> Either the ankyrin repeats alone or the AAA+ domain were found to be insufficient to support disaggregation activity.<ref name=":0" /> 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.<ref name="pmid15550237">{{cite journal | vauthors = Horwich AL | title = Chaperoned protein disaggregation--the ClpB ring uses its central channel | journal = Cell | volume = 119 | issue = 5 | pages = 579–81 | date = November 2004 | pmid = 15550237 | doi = 10.1016/j.cell.2004.11.018 | doi-access = free }}</ref><ref name="pmid15550247">{{cite journal | vauthors = 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 | title = Thermotolerance requires refolding of aggregated proteins by substrate translocation through the central pore of ClpB | journal = Cell | volume = 119 | issue = 5 | pages = 653–65 | date = November 2004 | pmid = 15550247 | doi = 10.1016/j.cell.2004.11.027 | doi-access = free }}</ref><ref name="pmid25288401">{{cite journal | vauthors = Nakazaki Y, Watanabe YH | title = ClpB chaperone passively threads soluble denatured proteins through its central pore | journal = Genes to Cells | volume = 19 | issue = 12 | pages = 891–900 | date = December 2014 | pmid = 25288401 | doi = 10.1111/gtc.12188 | s2cid = 7170147 | doi-access = free }}</ref> />
== 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.<ref name="pmid25650066"/> 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.<ref name="pmid25597510"/><ref name="pmid26916670"/><ref name="pmid27290639">{{cite journal | vauthors = 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 | title = New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre | journal = Journal of Translational Medicine | volume = 14 | issue = 1 | page = 174 | date = 12 June 2016 | pmid = 27290639 | doi = 10.1186/s12967-016-0930-9 | pmc=4903158 | doi-access = free }}</ref> Further investigation into Skd3 may shed a new light on the diagnosis of this disease.
== Interactions ==
This protein is known to interact with: *HAX1<ref name="pmid25597510"/><ref name=":0" /><ref name=":2" /> *PARL<ref name=":0" /><ref name=":1" /> *HTRA2<ref name=":0" /> *SMAC/DIABLO<ref name=":0" /> *OPA1<ref name=":0" /> *OPA3<ref name=":2" /> *PHB2<ref name=":0" /><ref>{{Cite journal|last1=Yoshinaka|first1=Takahiro|last2=Kosako|first2=Hidetaka|last3=Yoshizumi|first3=Takuma|last4=Furukawa|first4=Ryo|last5=Hirano|first5=Yu|last6=Kuge|first6=Osamu|last7=Tamada|first7=Taro|last8=Koshiba|first8=Takumi|date=2019-09-27|title=Structural Basis of Mitochondrial Scaffolds by Prohibitin Complexes: Insight into a Role of the Coiled-Coil Region|url= |journal=iScience|language=en|volume=19|pages=1065–1078|doi=10.1016/j.isci.2019.08.056|issn=2589-0042|pmc=6745515|pmid=31522117|bibcode=2019iSci...19.1065Y}}</ref> *MICU1<ref name=":0" /> *MICU2<ref name=":0" /> *SLC25A25<ref name=":0" /> *SLC25A13<ref name=":0" /> *TIMM8A<ref name=":0" /> *TIMM8B<ref name=":0" /> *TIMM13<ref name=":0" /> *TIMM21<ref name=":0" /> *TIMM22<ref name=":0" /> *TIMM23<ref name=":0" /> *TIMM50<ref name=":0" /> *NDUFA8<ref name=":0" /> *NDUFA11<ref name=":0" /> *NDUFA13<ref name=":0" /> *NDUFB7<ref name=":0" /> *NDUFB10<ref name=":0" /> *TTC19<ref name=":0" /> *COX11<ref name=":0" /> *CYC1<ref name=":0" />
== References == {{reflist|33em}}
==External links== * {{UCSC gene info|clpB}}
== Further reading == {{refbegin|33em}} * {{cite journal | vauthors = 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 | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | date = October 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | bibcode = 2005Natur.437.1173R | s2cid = 4427026 }} * {{cite journal | vauthors = Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM | title = Functional proteomics mapping of a human signaling pathway | journal = Genome Research | volume = 14 | issue = 7 | pages = 1324–32 | date = July 2004 | pmid = 15231748 | pmc = 442148 | doi = 10.1101/gr.2334104 }} * {{cite journal | vauthors = Leonard D, Ajuh P, Lamond AI, Legerski RJ | title = hLodestar/HuF2 interacts with CDC5L and is involved in pre-mRNA splicing | journal = Biochemical and Biophysical Research Communications | volume = 308 | issue = 4 | pages = 793–801 | date = September 2003 | pmid = 12927788 | doi = 10.1016/S0006-291X(03)01486-4 | citeseerx = 10.1.1.539.8359 }} {{refend}}
Category:Molecular chaperones