TIM22_HUMAN
ID TIM22_HUMAN Reviewed; 194 AA.
AC Q9Y584; Q9NWI8;
DT 11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-2002, sequence version 2.
DT 03-AUG-2022, entry version 164.
DE RecName: Full=Mitochondrial import inner membrane translocase subunit Tim22;
DE AltName: Full=Testis-expressed protein 4;
GN Name=TIMM22; Synonyms=TEX4, TIM22;
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].
RX PubMed=10611480; DOI=10.1016/s0014-5793(99)01665-8;
RA Bauer M.F., Rothbauer U., Muehlenbein N., Smith R.J.H., Gerbitz K.-D.,
RA Neupert W., Brunner M., Hofmann S.;
RT "The mitochondrial TIM22 preprotein translocase is highly conserved
RT throughout the eukaryotic kingdom.";
RL FEBS Lett. 464:41-47(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Adipose tissue;
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 MRNA].
RC TISSUE=Lung;
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 [4]
RP INTERACTION WITH TIMM9; TIMM10A AND TIMM10B.
RX PubMed=14726512; DOI=10.1074/jbc.m312485200;
RA Muehlenbein N., Hofmann S., Rothbauer U., Bauer M.F.;
RT "Organization and function of the small Tim complexes acting along the
RT import pathway of metabolite carriers into mammalian mitochondria.";
RL J. Biol. Chem. 279:13540-13546(2004).
RN [5]
RP CHARACTERIZATION.
RA Muehlenbein N.;
RT "Characterisation of the mitochondrial human Tim22-translocase.";
RL Thesis (2005), University of Munich, Germany.
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 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 INTERACTION WITH TIMM29, AND IDENTIFICATION IN THE TIM22 COMPLEX.
RX PubMed=27718247; DOI=10.1002/1873-3468.12450;
RA Callegari S., Richter F., Chojnacka K., Jans D.C., Lorenzi I.,
RA Pacheu-Grau D., Jakobs S., Lenz C., Urlaub H., Dudek J., Chacinska A.,
RA Rehling P.;
RT "TIM29 is a subunit of the human carrier translocase required for protein
RT transport.";
RL FEBS Lett. 590:4147-4158(2016).
RN [9]
RP DISULFIDE BOND, SUBCELLULAR LOCATION, AND IDENTIFICATION IN THE TIM22
RP COMPLEX.
RX PubMed=27265872; DOI=10.1038/srep27484;
RA Wrobel L., Sokol A.M., Chojnacka M., Chacinska A.;
RT "The presence of disulfide bonds reveals an evolutionarily conserved
RT mechanism involved in mitochondrial protein translocase assembly.";
RL Sci. Rep. 6:27484-27484(2016).
RN [10]
RP IDENTIFICATION IN THE TIM22 COMPLEX.
RX PubMed=28712724; DOI=10.1016/j.molcel.2017.06.013;
RA Vukotic M., Nolte H., Koenig T., Saita S., Ananjew M., Krueger M.,
RA Tatsuta T., Langer T.;
RT "Acylglycerol kinase mutated in Sengers Syndrome is a subunit of the TIM22
RT protein translocase in mitochondria.";
RL Mol. Cell 0:0-0(2017).
RN [11]
RP IDENTIFICATION IN THE TIM22 COMPLEX.
RX PubMed=28712726; DOI=10.1016/j.molcel.2017.06.014;
RA Kang Y., Stroud D.A., Baker M.J., De Souza D.P., Frazier A.E., Liem M.,
RA Tull D., Mathivanan S., McConville M.J., Thorburn D.R., Ryan M.T.,
RA Stojanovski D.;
RT "Sengers syndrome-associated mitochondrial acylglycerol kinase is a subunit
RT of the human TIM22 protein import complex.";
RL Mol. Cell 0:0-0(2017).
RN [12]
RP INVOLVEMENT IN COXPD43, VARIANTS COXPD43 25-TYR--ARG-194 DEL AND LEU-33,
RP AND CHARACTERIZATION OF VARIANT COXPD43 LEU-33.
RX PubMed=30452684; DOI=10.1093/hmg/ddy305;
RA Pacheu-Grau D., Callegari S., Emperador S., Thompson K., Aich A.,
RA Topol S.E., Spencer E.G., McFarland R., Ruiz-Pesini E., Torkamani A.,
RA Taylor R.W., Montoya J., Rehling P.;
RT "Mutations of the mitochondrial carrier translocase channel subunit TIM22
RT cause early-onset mitochondrial myopathy.";
RL Hum. Mol. Genet. 27:4135-4144(2018).
CC -!- FUNCTION: Essential core component of the TIM22 complex, a complex that
CC mediates the import and insertion of multi-pass transmembrane proteins
CC into the mitochondrial inner membrane. In the TIM22 complex, it
CC constitutes the voltage-activated and signal-gated channel. Forms a
CC twin-pore translocase that uses the membrane potential as external
CC driving force in 2 voltage-dependent steps (By similarity).
CC {ECO:0000250|UniProtKB:Q12328}.
CC -!- SUBUNIT: Component of the TIM22 complex, whose core is composed of
CC TIMM22, associated with peripheral protein FXC1/TIMM10B and the 70 kDa
CC heterohexamer (PubMed:14726512, PubMed:27265872). In most cases, the 70
CC kDa complex is composed of TIMM9 and TIMM10 (TIMM10A or TIMM10B)
CC (PubMed:14726512). A small fraction of the 70 kDa complex is composed
CC of TIMM8 (TIMM8A/DDP1 or TIMM8B/DDP2) and TIMM13 (PubMed:14726512). The
CC TIM22 complex also contains AGK and TIMM29 (PubMed:27718247,
CC PubMed:28712724, PubMed:28712726). Interacts directly with TIMM9,
CC TIMM10A and FXC1/TIMM10B (PubMed:14726512). Interacts (when oxidized)
CC with TIMM29; interaction is direct (PubMed:27718247).
CC {ECO:0000269|PubMed:14726512, ECO:0000269|PubMed:27265872,
CC ECO:0000269|PubMed:27718247}.
CC -!- INTERACTION:
CC Q9Y584; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-1200494, EBI-3867333;
CC Q9Y584; Q9H6H4: REEP4; NbExp=3; IntAct=EBI-1200494, EBI-7545592;
CC Q9Y584; Q9NUH8: TMEM14B; NbExp=3; IntAct=EBI-1200494, EBI-8638294;
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000269|PubMed:27265872}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- PTM: Disulfide bonds promote efficient assembly of the TIM22 complex.
CC {ECO:0000269|PubMed:27265872}.
CC -!- DISEASE: Combined oxidative phosphorylation deficiency 43 (COXPD43)
CC [MIM:618851]: An autosomal recessive mitochondrial disorder
CC characterized by onset at birth, intrauterine growth retardation,
CC hypotonia, myopathy, feeding difficulties associated with
CC gastroesophageal reflux, and persistently elevated serum lactate and
CC creatine kinase. Brain imaging shows delayed myelination. Muscle biopsy
CC shows decreased activities of mitochondrial respiratory chain complexes
CC I, III, and IV. {ECO:0000269|PubMed:30452684}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the Tim17/Tim22/Tim23 family. {ECO:0000305}.
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DR EMBL; AF155330; AAD40106.1; -; mRNA.
DR EMBL; AK000830; BAA91392.1; -; mRNA.
DR EMBL; BC002324; AAH02324.1; -; mRNA.
DR CCDS; CCDS32521.1; -.
DR RefSeq; NP_037469.2; NM_013337.3.
DR PDB; 7CGP; EM; 3.70 A; A=1-194.
DR PDBsum; 7CGP; -.
DR AlphaFoldDB; Q9Y584; -.
DR SMR; Q9Y584; -.
DR BioGRID; 118969; 15.
DR ComplexPortal; CPX-6124; TIM22 mitochondrial inner membrane twin-pore carrier translocase complex.
DR IntAct; Q9Y584; 6.
DR STRING; 9606.ENSP00000320236; -.
DR iPTMnet; Q9Y584; -.
DR PhosphoSitePlus; Q9Y584; -.
DR BioMuta; TIMM22; -.
DR DMDM; 24638462; -.
DR EPD; Q9Y584; -.
DR jPOST; Q9Y584; -.
DR MassIVE; Q9Y584; -.
DR MaxQB; Q9Y584; -.
DR PaxDb; Q9Y584; -.
DR PeptideAtlas; Q9Y584; -.
DR PRIDE; Q9Y584; -.
DR ProteomicsDB; 86313; -.
DR Antibodypedia; 22666; 29 antibodies from 15 providers.
DR DNASU; 29928; -.
DR Ensembl; ENST00000327158.5; ENSP00000320236.2; ENSG00000177370.5.
DR Ensembl; ENST00000613269.2; ENSP00000482204.1; ENSG00000278501.2.
DR Ensembl; ENST00000617832.2; ENSP00000478463.1; ENSG00000277649.2.
DR GeneID; 29928; -.
DR KEGG; hsa:29928; -.
DR MANE-Select; ENST00000327158.5; ENSP00000320236.2; NM_013337.4; NP_037469.2.
DR UCSC; uc002fsc.4; human.
DR CTD; 29928; -.
DR DisGeNET; 29928; -.
DR GeneCards; TIMM22; -.
DR HGNC; HGNC:17317; TIMM22.
DR HPA; ENSG00000177370; Low tissue specificity.
DR MalaCards; TIMM22; -.
DR MIM; 607251; gene.
DR MIM; 618851; phenotype.
DR neXtProt; NX_Q9Y584; -.
DR OpenTargets; ENSG00000177370; -.
DR PharmGKB; PA38230; -.
DR VEuPathDB; HostDB:ENSG00000177370; -.
DR eggNOG; KOG3225; Eukaryota.
DR GeneTree; ENSGT00390000016067; -.
DR HOGENOM; CLU_091077_0_0_1; -.
DR InParanoid; Q9Y584; -.
DR OMA; THSYAKN; -.
DR OrthoDB; 1544601at2759; -.
DR PhylomeDB; Q9Y584; -.
DR TreeFam; TF105836; -.
DR PathwayCommons; Q9Y584; -.
DR Reactome; R-HSA-1268020; Mitochondrial protein import.
DR SignaLink; Q9Y584; -.
DR SIGNOR; Q9Y584; -.
DR BioGRID-ORCS; 29928; 386 hits in 1088 CRISPR screens.
DR ChiTaRS; TIMM22; human.
DR GeneWiki; TIMM22; -.
DR GenomeRNAi; 29928; -.
DR Pharos; Q9Y584; Tbio.
DR PRO; PR:Q9Y584; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q9Y584; protein.
DR Bgee; ENSG00000177370; Expressed in apex of heart and 100 other tissues.
DR Genevisible; Q9Y584; HS.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:ComplexPortal.
DR GO; GO:0042721; C:TIM22 mitochondrial import inner membrane insertion complex; IDA:UniProtKB.
DR GO; GO:0030943; F:mitochondrion targeting sequence binding; IBA:GO_Central.
DR GO; GO:0008320; F:protein transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:0140318; F:protein transporter activity; IMP:FlyBase.
DR GO; GO:0045039; P:protein insertion into mitochondrial inner membrane; IDA:UniProtKB.
DR InterPro; IPR039175; TIM22.
DR PANTHER; PTHR14110; PTHR14110; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Disease variant; Disulfide bond; Membrane; Mitochondrion;
KW Mitochondrion inner membrane; Primary mitochondrial disease;
KW Protein transport; Reference proteome; Translocation; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..194
FT /note="Mitochondrial import inner membrane translocase
FT subunit Tim22"
FT /id="PRO_0000210298"
FT TRANSMEM 74..94
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 123..143
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 170..190
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DISULFID 69..141
FT /evidence="ECO:0000269|PubMed:27265872"
FT DISULFID 160..179
FT /evidence="ECO:0000269|PubMed:27265872"
FT VARIANT 25..194
FT /note="Missing (in COXPD43)"
FT /evidence="ECO:0000269|PubMed:30452684"
FT /id="VAR_084014"
FT VARIANT 33
FT /note="V -> L (in COXPD43; affects assembly or stability of
FT the translocase)"
FT /evidence="ECO:0000269|PubMed:30452684"
FT /id="VAR_084015"
FT CONFLICT 117..118
FT /note="DM -> EH (in Ref. 1; AAD40106)"
FT /evidence="ECO:0000305"
FT CONFLICT 140
FT /note="E -> W (in Ref. 1; AAD40106)"
FT /evidence="ECO:0000305"
FT CONFLICT 152
FT /note="W -> L (in Ref. 1; AAD40106)"
FT /evidence="ECO:0000305"
FT CONFLICT 166..167
FT /note="IG -> YW (in Ref. 1; AAD40106)"
FT /evidence="ECO:0000305"
FT CONFLICT 177..178
FT /note="IG -> LL (in Ref. 1; AAD40106)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 194 AA; 20031 MW; A1E6DD9F7F7399D6 CRC64;
MAAAAPNAGG SAPETAGSAE APLQYSLLLQ YLVGDKRQPR LLEPGSLGGI PSPAKSEEQK
MIEKAMESCA FKAALACVGG FVLGGAFGVF TAGIDTNVGF DPKDPYRTPT AKEVLKDMGQ
RGMSYAKNFA IVGAMFSCTE CLIESYRGTS DWKNSVISGC ITGGAIGFRA GLKAGAIGCG
GFAAFSAAID YYLR
