ID   MIPEP_HUMAN             Reviewed;         713 AA.
AC   Q99797; Q5JV15; Q5T9Q9; Q96G65;
DT   15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT   26-FEB-2008, sequence version 2.
DT   24-JAN-2024, entry version 192.
DE   RecName: Full=Mitochondrial intermediate peptidase;
DE            Short=MIP;
DE            EC=3.4.24.59;
DE   Flags: Precursor;
GN   Name=MIPEP; Synonyms=MIP;
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 [MRNA], AND VARIANT GLY-488.
RC   TISSUE=Liver;
RX   PubMed=9073519; DOI=10.1006/geno.1996.4586;
RA   Chew A., Buck E.A., Peretz S., Sirugo G., Rinaldo P., Isaya G.;
RT   "Cloning, expression, and chromosomal assignment of the human mitochondrial
RT   intermediate peptidase gene (MIPEP).";
RL   Genomics 40:493-496(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLY-488.
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15057823; DOI=10.1038/nature02379;
RA   Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA   Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S.,
RA   Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P.,
RA   Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L.,
RA   Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P.,
RA   Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA   Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C.,
RA   Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P.,
RA   Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L.,
RA   Frankish A.G., Frankland J., French L., Garner P., Garnett J.,
RA   Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M.,
RA   Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D.,
RA   Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D.,
RA   Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S.,
RA   Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J.,
RA   Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA   Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S.,
RA   Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R.,
RA   Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W.,
RA   Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P.,
RA   Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L.,
RA   Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R.,
RA   Rogers J., Ross M.T.;
RT   "The DNA sequence and analysis of human chromosome 13.";
RL   Nature 428:522-528(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLY-488.
RC   TISSUE=Uterus;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-126, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19608861; DOI=10.1126/science.1175371;
RA   Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA   Olsen J.V., Mann M.;
RT   "Lysine acetylation targets protein complexes and co-regulates major
RT   cellular functions.";
RL   Science 325:834-840(2009).
RN   [6]
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   [7]
RP   INVOLVEMENT IN COXPD31, AND VARIANTS COXPD31 GLN-71; PHE-306; GLU-343;
RP   ASP-512 AND ARG-582.
RX   PubMed=27799064; DOI=10.1186/s13073-016-0360-6;
RA   Eldomery M.K., Akdemir Z.C., Voegtle F.N., Charng W.L., Mulica P.,
RA   Rosenfeld J.A., Gambin T., Gu S., Burrage L.C., Al Shamsi A., Penney S.,
RA   Jhangiani S.N., Zimmerman H.H., Muzny D.M., Wang X., Tang J., Medikonda R.,
RA   Ramachandran P.V., Wong L.J., Boerwinkle E., Gibbs R.A., Eng C.M.,
RA   Lalani S.R., Hertecant J., Rodenburg R.J., Abdul-Rahman O.A., Yang Y.,
RA   Xia F., Wang M.C., Lupski J.R., Meisinger C., Sutton V.R.;
RT   "MIPEP recessive variants cause a syndrome of left ventricular non-
RT   compaction, hypotonia, and infantile death.";
RL   Genome Med. 8:106-106(2016).
CC   -!- FUNCTION: Cleaves proteins, imported into the mitochondrion, to their
CC       mature size.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Release of an N-terminal octapeptide as second stage of
CC         processing of some proteins imported into the mitochondrion.;
CC         EC=3.4.24.59;
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC       Note=Binds 1 zinc ion. {ECO:0000250};
CC   -!- ACTIVITY REGULATION: Activity is divalent cation-dependent. It is
CC       stimulated by manganese, magnesium or calcium ions and reversibly
CC       inhibited by zinc, cobalt and iron (By similarity). {ECO:0000250}.
CC   -!- SUBUNIT: Monomer. {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion matrix.
CC   -!- DISEASE: Combined oxidative phosphorylation deficiency 31 (COXPD31)
CC       [MIM:617228]: An autosomal recessive, severe mitochondrial disease with
CC       multisystemic manifestations appearing soon after birth or in early
CC       infancy. Clinical features include left ventricular non-compaction,
CC       global developmental delay, severe hypotonia, seizures, cataract, and
CC       abnormal movements. Death may occur in early childhood.
CC       {ECO:0000269|PubMed:27799064}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the peptidase M3 family. {ECO:0000305}.
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DR   EMBL; U80034; AAC51231.1; -; mRNA.
DR   EMBL; AK291923; BAF84612.1; -; mRNA.
DR   EMBL; AL157368; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL139080; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL445985; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC009934; AAH09934.1; -; mRNA.
DR   CCDS; CCDS9303.1; -.
DR   RefSeq; NP_005923.2; NM_005932.3.
DR   AlphaFoldDB; Q99797; -.
DR   SMR; Q99797; -.
DR   BioGRID; 110431; 101.
DR   IntAct; Q99797; 32.
DR   MINT; Q99797; -.
DR   STRING; 9606.ENSP00000371607; -.
DR   MEROPS; M03.006; -.
DR   iPTMnet; Q99797; -.
DR   MetOSite; Q99797; -.
DR   PhosphoSitePlus; Q99797; -.
DR   SwissPalm; Q99797; -.
DR   BioMuta; MIPEP; -.
DR   DMDM; 182639267; -.
DR   EPD; Q99797; -.
DR   jPOST; Q99797; -.
DR   MassIVE; Q99797; -.
DR   MaxQB; Q99797; -.
DR   PaxDb; 9606-ENSP00000371607; -.
DR   PeptideAtlas; Q99797; -.
DR   ProteomicsDB; 78477; -.
DR   Pumba; Q99797; -.
DR   Antibodypedia; 22428; 455 antibodies from 28 providers.
DR   DNASU; 4285; -.
DR   Ensembl; ENST00000382172.4; ENSP00000371607.3; ENSG00000027001.10.
DR   GeneID; 4285; -.
DR   KEGG; hsa:4285; -.
DR   MANE-Select; ENST00000382172.4; ENSP00000371607.3; NM_005932.4; NP_005923.3.
DR   UCSC; uc001uox.5; human.
DR   AGR; HGNC:7104; -.
DR   CTD; 4285; -.
DR   DisGeNET; 4285; -.
DR   GeneCards; MIPEP; -.
DR   HGNC; HGNC:7104; MIPEP.
DR   HPA; ENSG00000027001; Low tissue specificity.
DR   MalaCards; MIPEP; -.
DR   MIM; 602241; gene.
DR   MIM; 617228; phenotype.
DR   neXtProt; NX_Q99797; -.
DR   OpenTargets; ENSG00000027001; -.
DR   Orphanet; 478049; Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome.
DR   PharmGKB; PA30822; -.
DR   VEuPathDB; HostDB:ENSG00000027001; -.
DR   eggNOG; KOG2090; Eukaryota.
DR   GeneTree; ENSGT00950000183171; -.
DR   HOGENOM; CLU_001805_0_2_1; -.
DR   InParanoid; Q99797; -.
DR   OMA; ALMFEYM; -.
DR   OrthoDB; 735202at2759; -.
DR   PhylomeDB; Q99797; -.
DR   TreeFam; TF105715; -.
DR   PathwayCommons; Q99797; -.
DR   SignaLink; Q99797; -.
DR   BioGRID-ORCS; 4285; 275 hits in 1159 CRISPR screens.
DR   ChiTaRS; MIPEP; human.
DR   GenomeRNAi; 4285; -.
DR   Pharos; Q99797; Tbio.
DR   PRO; PR:Q99797; -.
DR   Proteomes; UP000005640; Chromosome 13.
DR   RNAct; Q99797; Protein.
DR   Bgee; ENSG00000027001; Expressed in right atrium auricular region and 162 other cell types or tissues.
DR   GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR   GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0004222; F:metalloendopeptidase activity; IBA:GO_Central.
DR   GO; GO:0006518; P:peptide metabolic process; IBA:GO_Central.
DR   GO; GO:0006627; P:protein processing involved in protein targeting to mitochondrion; IBA:GO_Central.
DR   CDD; cd06457; M3A_MIP; 1.
DR   Gene3D; 1.10.1370.40; -; 1.
DR   Gene3D; 3.40.390.10; Collagenase (Catalytic Domain); 1.
DR   Gene3D; 1.10.1370.10; Neurolysin, domain 3; 1.
DR   InterPro; IPR033851; M3A_MIP.
DR   InterPro; IPR024079; MetalloPept_cat_dom_sf.
DR   InterPro; IPR024077; Neurolysin/TOP_dom2.
DR   InterPro; IPR045090; Pept_M3A_M3B.
DR   InterPro; IPR001567; Pept_M3A_M3B_dom.
DR   PANTHER; PTHR11804:SF79; MITOCHONDRIAL INTERMEDIATE PEPTIDASE; 1.
DR   PANTHER; PTHR11804; PROTEASE M3 THIMET OLIGOPEPTIDASE-RELATED; 1.
DR   Pfam; PF01432; Peptidase_M3; 1.
DR   SUPFAM; SSF55486; Metalloproteases ('zincins'), catalytic domain; 1.
DR   PROSITE; PS00142; ZINC_PROTEASE; 1.
DR   Genevisible; Q99797; HS.
PE   1: Evidence at protein level;
KW   Acetylation; Calcium; Cobalt; Disease variant; Hydrolase; Iron; Magnesium;
KW   Manganese; Metal-binding; Metalloprotease; Mitochondrion;
KW   Primary mitochondrial disease; Protease; Reference proteome;
KW   Transit peptide; Zinc.
FT   TRANSIT         1..35
FT                   /note="Mitochondrion"
FT   CHAIN           36..713
FT                   /note="Mitochondrial intermediate peptidase"
FT                   /id="PRO_0000028579"
FT   ACT_SITE        496
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT   BINDING         495
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT   BINDING         499
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT   BINDING         502
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT   MOD_RES         126
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   VARIANT         71
FT                   /note="L -> Q (in COXPD31; dbSNP:rs1057518740)"
FT                   /evidence="ECO:0000269|PubMed:27799064"
FT                   /id="VAR_078009"
FT   VARIANT         137
FT                   /note="A -> V (in dbSNP:rs2312296)"
FT                   /id="VAR_038934"
FT   VARIANT         306
FT                   /note="L -> F (in COXPD31; dbSNP:rs143912947)"
FT                   /evidence="ECO:0000269|PubMed:27799064"
FT                   /id="VAR_078010"
FT   VARIANT         340
FT                   /note="R -> Q (in dbSNP:rs11551114)"
FT                   /id="VAR_038935"
FT   VARIANT         343
FT                   /note="K -> E (in COXPD31; dbSNP:rs1057518741)"
FT                   /evidence="ECO:0000269|PubMed:27799064"
FT                   /id="VAR_078011"
FT   VARIANT         453
FT                   /note="R -> H (in dbSNP:rs12858248)"
FT                   /id="VAR_038936"
FT   VARIANT         488
FT                   /note="S -> G (in dbSNP:rs7333040)"
FT                   /evidence="ECO:0000269|PubMed:14702039,
FT                   ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:9073519"
FT                   /id="VAR_038937"
FT   VARIANT         512
FT                   /note="H -> D (in COXPD31; uncertain significance;
FT                   dbSNP:rs779598020)"
FT                   /evidence="ECO:0000269|PubMed:27799064"
FT                   /id="VAR_078012"
FT   VARIANT         582
FT                   /note="L -> R (in COXPD31; uncertain significance;
FT                   dbSNP:rs1057518739)"
FT                   /evidence="ECO:0000269|PubMed:27799064"
FT                   /id="VAR_078013"
FT   CONFLICT        63..64
FT                   /note="RG -> AR (in Ref. 1; AAC51231)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        200
FT                   /note="E -> Q (in Ref. 1; AAC51231)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        348
FT                   /note="P -> A (in Ref. 1; AAC51231)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        467
FT                   /note="V -> L (in Ref. 1; AAC51231)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   713 AA;  80641 MW;  9DBB26B74355B9C1 CRC64;
     MLCVGRLGGL GARAAALPPR RAGRGSLEAG IRARRVSTSW SPVGAAFNVK PQGSRLDLFG
     ERRGLFGVPE LSAPEGFHIA QEKALRKTEL LVDRACSTPP GPQTVLIFDE LSDSLCRVAD
     LADFVKIAHP EPAFREAAEE ACRSIGTMVE KLNTNVDLYQ SLQKLLADKK LVDSLDPETR
     RVAELFMFDF EISGIHLDKE KRKRAVDLNV KILDLSSTFL MGTNFPNKIE KHLLPEHIRR
     NFTSAGDHII IDGLHAESPD DLVREAAYKI FLYPNAGQLK CLEELLSSRD LLAKLVGYST
     FSHRALQGTI AKNPETVMQF LEKLSDKLSE RTLKDFEMIR GMKMKLNPQN SEVMPWDPPY
     YSGVIRAERY NIEPSLYCPF FSLGACMEGL NILLNRLLGI SLYAEQPAKG EVWSEDVRKL
     AVVHESEGLL GYIYCDFFQR ADKPHQDCHF TIRGGRLKED GDYQLPVVVL MLNLPRSSRS
     SPTLLTPSMM ENLFHEMGHA MHSMLGRTRY QHVTGTRCPT DFAEVPSILM EYFANDYRVV
     NQFARHYQTG QPLPKNMVSR LCESKKVCAA ADMQLQVFYA TLDQIYHGKH PLRNSTTDIL
     KETQEKFYGL PYVPNTAWQL RFSHLVGYGA RYYSYLMSRA VASMVWKECF LQDPFNRAAG
     ERYRREMLAH GGGREPMLMV EGMLQKCPSV DDFVSALVSD LDLDFETFLM DSE
//