MPPB_HUMAN
ID MPPB_HUMAN Reviewed; 489 AA.
AC O75439; O60416; Q96FV4;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT 11-APR-2003, sequence version 2.
DT 03-AUG-2022, entry version 189.
DE RecName: Full=Mitochondrial-processing peptidase subunit beta;
DE EC=3.4.24.64 {ECO:0000305|PubMed:22354088};
DE AltName: Full=Beta-MPP;
DE AltName: Full=P-52;
DE Flags: Precursor;
GN Name=PMPCB; Synonyms=MPPB;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Umbilical cord blood;
RX PubMed=9653160; DOI=10.1073/pnas.95.14.8175;
RA Mao M., Fu G., Wu J.-S., Zhang Q.-H., Zhou J., Kan L.-X., Huang Q.-H.,
RA He K.-L., Gu B.-W., Han Z.-G., Shen Y., Gu J., Yu Y.-P., Xu S.-H.,
RA Wang Y.-X., Chen S.-J., Chen Z.;
RT "Identification of genes expressed in human CD34(+) hematopoietic
RT stem/progenitor cells by expressed sequence tags and efficient full-length
RT cDNA cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:8175-8180(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [3]
RP PROTEIN SEQUENCE [LARGE SCALE ANALYSIS] OF 44-60.
RC TISSUE=Leukemic T-cell;
RX PubMed=19892738; DOI=10.1073/pnas.0908958106;
RA Xu G., Shin S.B., Jaffrey S.R.;
RT "Global profiling of protease cleavage sites by chemoselective labeling of
RT protein N-termini.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:19310-19315(2009).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=22354088; DOI=10.1038/embor.2012.14;
RA Greene A.W., Grenier K., Aguileta M.A., Muise S., Farazifard R.,
RA Haque M.E., McBride H.M., Park D.S., Fon E.A.;
RT "Mitochondrial processing peptidase regulates PINK1 processing, import and
RT Parkin recruitment.";
RL EMBO Rep. 13:378-385(2012).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [8]
RP INVOLVEMENT IN MMDS6, VARIANTS MMDS6 CYS-175; HIS-175; GLY-177; PRO-201 AND
RP THR-422, CHARACTERIZATION OF VARIANTS MMDS6 CYS-175; HIS-175; GLY-177;
RP PRO-201 AND THR-422, AND FUNCTION.
RX PubMed=29576218; DOI=10.1016/j.ajhg.2018.02.014;
RA Voegtle F.N., Braendl B., Larson A., Pendziwiat M., Friederich M.W.,
RA White S.M., Basinger A., Kuecuekkoese C., Muhle H., Jaehn J.A., Keminer O.,
RA Helbig K.L., Delto C.F., Myketin L., Mossmann D., Burger N., Miyake N.,
RA Burnett A., van Baalen A., Lovell M.A., Matsumoto N., Walsh M., Yu H.C.,
RA Shinde D.N., Stephani U., Van Hove J.L.K., Mueller F.J., Helbig I.;
RT "Mutations in PMPCB encoding the catalytic subunit of the mitochondrial
RT presequence protease cause neurodegeneration in early childhood.";
RL Am. J. Hum. Genet. 102:557-573(2018).
CC -!- FUNCTION: Catalytic subunit of the essential mitochondrial processing
CC protease (MPP), which cleaves the mitochondrial sequence off newly
CC imported precursors proteins (PubMed:29576218) (Probable).
CC Preferentially, cleaves after an arginine at position P2 (By
CC similarity). Required for PINK1 turnover by coupling PINK1
CC mitochondrial import and cleavage, which results in subsequent PINK1
CC proteolysis (PubMed:22354088). {ECO:0000250|UniProtKB:Q03346,
CC ECO:0000269|PubMed:22354088, ECO:0000269|PubMed:29576218,
CC ECO:0000305|PubMed:22354088}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Release of N-terminal transit peptides from precursor proteins
CC imported into the mitochondrion, typically with Arg in position P2.;
CC EC=3.4.24.64; Evidence={ECO:0000305|PubMed:22354088};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P10507};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:P10507};
CC -!- ACTIVITY REGULATION: Binding to PMPCA is required for catalytic
CC activity. {ECO:0000250|UniProtKB:P10507}.
CC -!- SUBUNIT: Heterodimer of PMPCA (alpha) and PMPCB (beta) subunits,
CC forming the mitochondrial processing protease (MPP) in which PMPCA is
CC involved in substrate recognition and binding and PMPCB is the
CC catalytic subunit. {ECO:0000250|UniProtKB:P10507}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000269|PubMed:22354088}.
CC -!- DISEASE: Multiple mitochondrial dysfunctions syndrome 6 (MMDS6)
CC [MIM:617954]: An autosomal recessive, neurodegenerative disorder
CC characterized by basal ganglia lesions, cerebellar atrophy, and
CC neurologic regression in the first year of life. Common features
CC include truncal hypotonia, lack of independent ambulation, poor speech,
CC intellectual disability, and motor abnormalities, such as ataxia,
CC dystonia, and spasticity. {ECO:0000269|PubMed:29576218}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the peptidase M16 family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AF054182; AAC39915.1; -; mRNA.
DR EMBL; AC004668; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS5730.1; -.
DR RefSeq; NP_004270.2; NM_004279.2.
DR AlphaFoldDB; O75439; -.
DR SMR; O75439; -.
DR BioGRID; 114889; 362.
DR ComplexPortal; CPX-6243; Mitochondrial processing peptidase complex.
DR IntAct; O75439; 62.
DR MINT; O75439; -.
DR STRING; 9606.ENSP00000249269; -.
DR MEROPS; M16.973; -.
DR GlyGen; O75439; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O75439; -.
DR MetOSite; O75439; -.
DR PhosphoSitePlus; O75439; -.
DR SwissPalm; O75439; -.
DR BioMuta; PMPCB; -.
DR CPTAC; CPTAC-427; -.
DR EPD; O75439; -.
DR jPOST; O75439; -.
DR MassIVE; O75439; -.
DR MaxQB; O75439; -.
DR PaxDb; O75439; -.
DR PeptideAtlas; O75439; -.
DR PRIDE; O75439; -.
DR ProteomicsDB; 50007; -.
DR Antibodypedia; 31179; 189 antibodies from 27 providers.
DR DNASU; 9512; -.
DR Ensembl; ENST00000249269.9; ENSP00000249269.4; ENSG00000105819.14.
DR GeneID; 9512; -.
DR KEGG; hsa:9512; -.
DR MANE-Select; ENST00000249269.9; ENSP00000249269.4; NM_004279.3; NP_004270.2.
DR UCSC; uc003vbl.4; human.
DR CTD; 9512; -.
DR DisGeNET; 9512; -.
DR GeneCards; PMPCB; -.
DR HGNC; HGNC:9119; PMPCB.
DR HPA; ENSG00000105819; Low tissue specificity.
DR MalaCards; PMPCB; -.
DR MIM; 603131; gene.
DR MIM; 617954; phenotype.
DR neXtProt; NX_O75439; -.
DR OpenTargets; ENSG00000105819; -.
DR Orphanet; 569290; Multiple mitochondrial dysfunctions syndrome type 6.
DR PharmGKB; PA33445; -.
DR VEuPathDB; HostDB:ENSG00000105819; -.
DR eggNOG; KOG0960; Eukaryota.
DR GeneTree; ENSGT00940000156608; -.
DR HOGENOM; CLU_009902_4_0_1; -.
DR InParanoid; O75439; -.
DR OMA; IDVVCDM; -.
DR OrthoDB; 638125at2759; -.
DR PhylomeDB; O75439; -.
DR TreeFam; TF105032; -.
DR BRENDA; 3.4.24.64; 2681.
DR PathwayCommons; O75439; -.
DR Reactome; R-HSA-1268020; Mitochondrial protein import.
DR Reactome; R-HSA-8949664; Processing of SMDT1.
DR SignaLink; O75439; -.
DR SIGNOR; O75439; -.
DR BioGRID-ORCS; 9512; 713 hits in 1085 CRISPR screens.
DR ChiTaRS; PMPCB; human.
DR GeneWiki; PMPCB; -.
DR GenomeRNAi; 9512; -.
DR Pharos; O75439; Tbio.
DR PRO; PR:O75439; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; O75439; protein.
DR Bgee; ENSG00000105819; Expressed in right adrenal gland cortex and 206 other tissues.
DR ExpressionAtlas; O75439; baseline and differential.
DR Genevisible; O75439; HS.
DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome.
DR GO; GO:0017087; C:mitochondrial processing peptidase complex; IC:ComplexPortal.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004222; F:metalloendopeptidase activity; IDA:UniProtKB.
DR GO; GO:0006851; P:mitochondrial calcium ion transmembrane transport; TAS:Reactome.
DR GO; GO:0006627; P:protein processing involved in protein targeting to mitochondrion; IDA:UniProtKB.
DR InterPro; IPR011249; Metalloenz_LuxS/M16.
DR InterPro; IPR037718; MPP_beat.
DR InterPro; IPR011765; Pept_M16_N.
DR InterPro; IPR001431; Pept_M16_Zn_BS.
DR InterPro; IPR007863; Peptidase_M16_C.
DR PANTHER; PTHR11851:SF103; PTHR11851:SF103; 1.
DR Pfam; PF00675; Peptidase_M16; 1.
DR Pfam; PF05193; Peptidase_M16_C; 1.
DR SUPFAM; SSF63411; SSF63411; 2.
DR PROSITE; PS00143; INSULINASE; 1.
PE 1: Evidence at protein level;
KW Direct protein sequencing; Disease variant; Hydrolase; Metal-binding;
KW Metalloprotease; Mitochondrion; Neurodegeneration; Protease;
KW Reference proteome; Transit peptide; Zinc.
FT TRANSIT 1..43
FT /note="Mitochondrion"
FT /evidence="ECO:0000269|PubMed:19892738"
FT CHAIN 44..489
FT /note="Mitochondrial-processing peptidase subunit beta"
FT /id="PRO_0000026777"
FT ACT_SITE 104
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10096"
FT BINDING 101
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10096"
FT BINDING 105
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10096"
FT BINDING 181
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10096"
FT SITE 191
FT /note="Required for the specific determination of the
FT substrate cleavage site"
FT /evidence="ECO:0000250|UniProtKB:Q03346"
FT SITE 195
FT /note="Required for the specific determination of the
FT substrate cleavage site"
FT /evidence="ECO:0000250|UniProtKB:Q03346"
FT VARIANT 175
FT /note="R -> C (in MMDS6; exhibits temperature-sensitive
FT defect in presequence processing activity, when tested in
FT yeast; dbSNP:rs145596167)"
FT /evidence="ECO:0000269|PubMed:29576218"
FT /id="VAR_080804"
FT VARIANT 175
FT /note="R -> H (in MMDS6; exhibits temperature-sensitive
FT defect in presequence processing activity, when tested in
FT yeast; dbSNP:rs200188353)"
FT /evidence="ECO:0000269|PubMed:29576218"
FT /id="VAR_080805"
FT VARIANT 177
FT /note="V -> G (in MMDS6; exhibits temperature-sensitive
FT defect in presequence processing activity, when tested in
FT yeast; dbSNP:rs1436866272)"
FT /evidence="ECO:0000269|PubMed:29576218"
FT /id="VAR_080806"
FT VARIANT 201
FT /note="A -> P (in MMDS6; exhibits temperature-sensitive
FT defect in presequence processing activity, when tested in
FT yeast; dbSNP:rs146343535)"
FT /evidence="ECO:0000269|PubMed:29576218"
FT /id="VAR_080807"
FT VARIANT 396
FT /note="E -> D (in dbSNP:rs3087615)"
FT /id="VAR_051572"
FT VARIANT 422
FT /note="I -> T (in MMDS6; small decrease in protein level;
FT impaired frataxin/FXN processing, leading to the
FT accumulation of an intermediate form, called iFXN;
FT dbSNP:rs1461200360)"
FT /evidence="ECO:0000269|PubMed:29576218"
FT /id="VAR_080808"
FT CONFLICT 16..17
FT /note="RR -> GG (in Ref. 1; AAC39915)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 489 AA; 54366 MW; 79250D016E60CFEE CRC64;
MAAAAARVVL SSAARRRLWG FSESLLIRGA AGRSLYFGEN RLRSTQAATQ VVLNVPETRV
TCLESGLRVA SEDSGLSTCT VGLWIDAGSR YENEKNNGTA HFLEHMAFKG TKKRSQLDLE
LEIENMGAHL NAYTSREQTV YYAKAFSKDL PRAVEILADI IQNSTLGEAE IERERGVILR
EMQEVETNLQ EVVFDYLHAT AYQNTALGRT ILGPTENIKS ISRKDLVDYI TTHYKGPRIV
LAAAGGVSHD ELLDLAKFHF GDSLCTHKGE IPALPPCKFT GSEIRVRDDK MPLAHLAIAV
EAVGWAHPDT ICLMVANTLI GNWDRSFGGG MNLSSKLAQL TCHGNLCHSF QSFNTSYTDT
GLWGLYMVCE SSTVADMLHV VQKEWMRLCT SVTESEVARA RNLLKTNMLL QLDGSTPICE
DIGRQMLCYN RRIPIPELEA RIDAVNAETI REVCTKYIYN RSPAIAAVGP IKQLPDFKQI
RSNMCWLRD
