MMAA_HUMAN
ID MMAA_HUMAN Reviewed; 418 AA.
AC Q8IVH4; B3KX40; Q495G7;
DT 07-NOV-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=Methylmalonic aciduria type A protein, mitochondrial {ECO:0000305};
DE EC=3.6.-.- {ECO:0000269|PubMed:20876572, ECO:0000269|PubMed:21138732, ECO:0000269|PubMed:28497574, ECO:0000269|PubMed:28943303};
DE Flags: Precursor;
GN Name=MMAA {ECO:0000312|HGNC:HGNC:18871};
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 [GENOMIC DNA], AND VARIANT MMAA CYS-207.
RX PubMed=12438653; DOI=10.1073/pnas.242614799;
RA Dobson C.M., Wai T., Leclerc D., Wilson A., Wu X., Dore C., Hudson T.,
RA Rosenblatt D.S., Gravel R.A.;
RT "Identification of the gene responsible for the cblA complementation group
RT of vitamin B12-responsive methylmalonic acidemia based on analysis of
RT prokaryotic gene arrangements.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:15554-15559(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
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].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH MMUT.
RX PubMed=21138732; DOI=10.1016/j.bbrc.2010.11.141;
RA Takahashi-Iniguez T., Garcia-Arellano H., Trujillo-Roldan M.A.,
RA Flores M.E.;
RT "Protection and reactivation of human methylmalonyl-CoA mutase by MMAA
RT protein.";
RL Biochem. Biophys. Res. Commun. 404:443-447(2011).
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 FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND INTERACTION WITH
RP MMUT.
RX PubMed=28943303; DOI=10.1016/j.biochi.2017.09.012;
RA Takahashi-Iniguez T., Gonzalez-Noriega A., Michalak C., Flores M.E.;
RT "Human MMAA induces the release of inactive cofactor and restores
RT methylmalonyl-CoA mutase activity through their complex formation.";
RL Biochimie 142:191-196(2017).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.64 ANGSTROMS) OF 72-418 IN COMPLEX WITH GDP,
RP SUBUNIT, BIOPHYSICOCHEMICAL PROPERTIES, INTERACTION WITH MMUT, FUNCTION,
RP CHARACTERIZATION OF VARIANT MMAA ARG-188, ACTIVITY REGULATION, CATALYTIC
RP ACTIVITY, AND GTP-BINDING.
RX PubMed=20876572; DOI=10.1074/jbc.m110.177717;
RA Froese D.S., Kochan G., Muniz J.R., Wu X., Gileadi C., Ugochukwu E.,
RA Krysztofinska E., Gravel R.A., Oppermann U., Yue W.W.;
RT "Structures of the human GTPase MMAA and vitamin B12-dependent
RT methylmalonyl-CoA mutase and insight into their complex formation.";
RL J. Biol. Chem. 285:38204-38213(2010).
RN [10]
RP VARIANTS MMAA 22-ARG--ASP-418 DEL; 54-TRP--ASP-418 DEL; PRO-89;
RP 129-TYR--ASP-418 DEL; 145-ARG--ASP-418 DEL; GLN-145; GLU-147; CYS-207;
RP GLU-218; 248-GLN--ASP-418 DEL; 320-TRP--ASP-418 DEL; 330-ARG--ASP-418 DEL
RP AND GLN-359, AND VARIANT HIS-363.
RX PubMed=15523652; DOI=10.1002/humu.20104;
RA Lerner-Ellis J.P., Dobson C.M., Wai T., Watkins D., Tirone J.C.,
RA Leclerc D., Dore C., Lepage P., Gravel R.A., Rosenblatt D.S.;
RT "Mutations in the MMAA gene in patients with the cblA disorder of vitamin
RT B(12) metabolism.";
RL Hum. Mutat. 24:509-516(2004).
RN [11]
RP VARIANT MMAA GLY-359.
RX PubMed=15308131; DOI=10.1016/j.ymgme.2004.05.002;
RA Yang X., Sakamoto O., Matsubara Y., Kure S., Suzuki Y., Aoki Y., Suzuki Y.,
RA Sakura N., Takayanagi M., Iinuma K., Ohura T.;
RT "Mutation analysis of the MMAA and MMAB genes in Japanese patients with
RT vitamin B(12)-responsive methylmalonic acidemia: identification of a
RT prevalent MMAA mutation.";
RL Mol. Genet. Metab. 82:329-333(2004).
RN [12]
RP VARIANTS MMAA 22-ARG--ASP-418 DEL; 120-GLN--ASP-418 DEL; 133-GLN--ASP-418
RP DEL; 145-ARG--ASP-418 DEL AND ARG-188.
RX PubMed=17957493; DOI=10.1007/s10545-007-0667-y;
RA Merinero B., Perez B., Perez-Cerda C., Rincon A., Desviat L.R.,
RA Martinez M.A., Sala P.R., Garcia M.J., Aldamiz-Echevarria L., Campos J.,
RA Cornejo V., Del Toro M., Mahfoud A., Martinez-Pardo M., Parini R.,
RA Pedron C., Pena-Quintana L., Perez M., Pourfarzam M., Ugarte M.;
RT "Methylmalonic acidaemia: examination of genotype and biochemical data in
RT 32 patients belonging to mut, cblA or cblB complementation group.";
RL J. Inherit. Metab. Dis. 31:55-66(2008).
RN [13]
RP VARIANTS MMAA SER-209; LYS-250; ASP-274; SER-274; GLU-276 AND GLN-359.
RX PubMed=23026888; DOI=10.1016/j.ymgme.2012.09.012;
RA Dempsey-Nunez L., Illson M.L., Kent J., Huang Q., Brebner A., Watkins D.,
RA Gilfix B.M., Wittwer C.T., Rosenblatt D.S.;
RT "High resolution melting analysis of the MMAA gene in patients with cblA
RT and in those with undiagnosed methylmalonic aciduria.";
RL Mol. Genet. Metab. 107:363-367(2012).
RN [14]
RP VARIANTS MMAA 24-TYR--ASP-418 DEL; 68-GLN--ASP-418 DEL; PRO-89;
RP 95-GLN--ASP-418 DEL; GLY-98; 100-CYS--ALA-104 DEL; 145-ARG--ASP-418 DEL;
RP GLN-145; GLU-147; ARG-188; ASP-192; 196-ARG--ASP-418 DEL; GLN-196; CYS-207;
RP SER-209; GLU-218; MET-220; PHE-241; ASN-243; 248-GLN--ASP-418 DEL; LYS-250;
RP ASN-258; SER-274; GLU-276; ASP-287; VAL-292; 330-ARG--ASP-418 DEL;
RP 359-ARG--ASP-418 DEL; GLN-359; GLY-359 AND VAL-399, CHARACTERIZATION OF
RP VARIANTS MMAA PRO-89; GLY-98; GLN-145; GLU-147; ARG-188; ASP-192; GLN-196;
RP CYS-207; SER-209; GLU-218; MET-220; PHE-241; ASN-243; LYS-250; SER-274;
RP GLU-276; ASP-287; VAL-292; GLN-359; GLY-359 AND VAL-399, FUNCTION,
RP GTP-BINDING, MUTAGENESIS OF LYS-290 AND ASP-292, BIOPHYSICOCHEMICAL
RP PROPERTIES, ACTIVITY REGULATION, AND CATALYTIC ACTIVITY.
RX PubMed=28497574; DOI=10.1002/humu.23251;
RA Plessl T., Buerer C., Lutz S., Yue W.W., Baumgartner M.R., Froese D.S.;
RT "Protein destabilization and loss of protein-protein interaction are
RT fundamental mechanisms in cblA-type methylmalonic aciduria.";
RL Hum. Mutat. 38:988-1001(2017).
CC -!- FUNCTION: GTPase, binds and hydrolyzes GTP (PubMed:28497574,
CC PubMed:20876572, PubMed:21138732, PubMed:28943303). Involved in
CC intracellular vitamin B12 metabolism, mediates the transport of
CC cobalamin (Cbl) into mitochondria for the final steps of
CC adenosylcobalamin (AdoCbl) synthesis (PubMed:28497574,
CC PubMed:20876572). Functions as a G-protein chaperone that assists
CC AdoCbl cofactor delivery from MMAB to the methylmalonyl-CoA mutase
CC (MMUT) (PubMed:28497574, PubMed:20876572). Plays a dual role as both a
CC protectase and a reactivase for MMUT (PubMed:21138732,
CC PubMed:28943303). Protects MMUT from progressive inactivation by
CC oxidation by decreasing the rate of the formation of the oxidized
CC inactive cofactor hydroxocobalamin (OH2Cbl) (PubMed:21138732,
CC PubMed:28943303). Additionally acts a reactivase by promoting the
CC replacement of OH2Cbl by the active cofactor AdoCbl, restoring the
CC activity of MMUT in the presence and hydrolysis of GTP
CC (PubMed:21138732, PubMed:28943303). {ECO:0000269|PubMed:20876572,
CC ECO:0000269|PubMed:21138732, ECO:0000269|PubMed:28497574,
CC ECO:0000269|PubMed:28943303}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=GTP + H2O = GDP + H(+) + phosphate; Xref=Rhea:RHEA:19669,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58189;
CC Evidence={ECO:0000269|PubMed:20876572, ECO:0000269|PubMed:21138732,
CC ECO:0000269|PubMed:28497574, ECO:0000269|PubMed:28943303};
CC -!- ACTIVITY REGULATION: GTPase activity is stimulated by MMUT.
CC {ECO:0000269|PubMed:20876572, ECO:0000269|PubMed:28497574}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=42 uM for GTP {ECO:0000269|PubMed:28497574};
CC KM=330 uM for GTP {ECO:0000269|PubMed:20876572};
CC KM=74 uM for GTP (in presence of MMUT) {ECO:0000269|PubMed:20876572};
CC Note=kcat is 0.201 min(-1) for GTP hydrolysis (PubMed:28497574). kcat
CC is 0.03 min(-1) for GTP hydrolysis (PubMed:20876572).
CC {ECO:0000269|PubMed:20876572, ECO:0000269|PubMed:28497574};
CC -!- SUBUNIT: Homodimer (PubMed:20876572). Interacts with MMUT (the
CC apoenzyme form); the interaction is GTP dependent (PubMed:20876572,
CC PubMed:28497574, PubMed:21138732, PubMed:28943303).
CC {ECO:0000269|PubMed:20876572, ECO:0000269|PubMed:21138732,
CC ECO:0000269|PubMed:28497574, ECO:0000269|PubMed:28943303}.
CC -!- INTERACTION:
CC Q8IVH4; Q8IVH4: MMAA; NbExp=2; IntAct=EBI-10714945, EBI-10714945;
CC Q8IVH4; P22033: MMUT; NbExp=3; IntAct=EBI-10714945, EBI-2690467;
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:28943303,
CC ECO:0000305}. Cytoplasm {ECO:0000269|PubMed:28943303}.
CC -!- TISSUE SPECIFICITY: Widely expressed. Highest expression is observed in
CC liver and skeletal muscle.
CC -!- DISEASE: Methylmalonic aciduria type cblA (MMAA) [MIM:251100]: A
CC disorder of methylmalonate and cobalamin metabolism due to defective
CC synthesis of adenosylcobalamin. {ECO:0000269|PubMed:12438653,
CC ECO:0000269|PubMed:15308131, ECO:0000269|PubMed:15523652,
CC ECO:0000269|PubMed:17957493, ECO:0000269|PubMed:20876572,
CC ECO:0000269|PubMed:23026888, ECO:0000269|PubMed:28497574}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the SIMIBI class G3E GTPase family. ArgK/MeaB
CC subfamily. {ECO:0000305}.
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DR EMBL; AF524846; AAN77287.1; -; Genomic_DNA.
DR EMBL; AF524841; AAN77287.1; JOINED; Genomic_DNA.
DR EMBL; AF524842; AAN77287.1; JOINED; Genomic_DNA.
DR EMBL; AF524843; AAN77287.1; JOINED; Genomic_DNA.
DR EMBL; AF524844; AAN77287.1; JOINED; Genomic_DNA.
DR EMBL; AF524845; AAN77287.1; JOINED; Genomic_DNA.
DR EMBL; AK126662; BAG54352.1; -; mRNA.
DR EMBL; CH471056; EAX05036.1; -; Genomic_DNA.
DR EMBL; BC101178; AAI01179.1; -; mRNA.
DR EMBL; BC101179; AAI01180.1; -; mRNA.
DR CCDS; CCDS3766.1; -.
DR RefSeq; NP_758454.1; NM_172250.2.
DR RefSeq; XP_011529986.1; XM_011531684.2.
DR RefSeq; XP_011529987.1; XM_011531685.2.
DR PDB; 2WWW; X-ray; 2.64 A; A/B/C/D=72-418.
DR PDBsum; 2WWW; -.
DR AlphaFoldDB; Q8IVH4; -.
DR SMR; Q8IVH4; -.
DR BioGRID; 127933; 5.
DR CORUM; Q8IVH4; -.
DR IntAct; Q8IVH4; 3.
DR STRING; 9606.ENSP00000281317; -.
DR DrugBank; DB00115; Cyanocobalamin.
DR DrugBank; DB00200; Hydroxocobalamin.
DR DrugCentral; Q8IVH4; -.
DR iPTMnet; Q8IVH4; -.
DR PhosphoSitePlus; Q8IVH4; -.
DR SwissPalm; Q8IVH4; -.
DR BioMuta; MMAA; -.
DR DMDM; 38258173; -.
DR EPD; Q8IVH4; -.
DR jPOST; Q8IVH4; -.
DR MassIVE; Q8IVH4; -.
DR MaxQB; Q8IVH4; -.
DR PaxDb; Q8IVH4; -.
DR PeptideAtlas; Q8IVH4; -.
DR PRIDE; Q8IVH4; -.
DR ProteomicsDB; 70708; -.
DR Antibodypedia; 27481; 159 antibodies from 20 providers.
DR DNASU; 166785; -.
DR Ensembl; ENST00000541599.5; ENSP00000442284.3; ENSG00000151611.17.
DR Ensembl; ENST00000648388.1; ENSP00000497046.1; ENSG00000151611.17.
DR Ensembl; ENST00000649156.2; ENSP00000497008.1; ENSG00000151611.17.
DR Ensembl; ENST00000649704.1; ENSP00000497680.1; ENSG00000151611.17.
DR Ensembl; ENST00000679563.1; ENSP00000506503.1; ENSG00000151611.17.
DR GeneID; 166785; -.
DR KEGG; hsa:166785; -.
DR MANE-Select; ENST00000649156.2; ENSP00000497008.1; NM_172250.3; NP_758454.1.
DR UCSC; uc003ikh.5; human.
DR CTD; 166785; -.
DR DisGeNET; 166785; -.
DR GeneCards; MMAA; -.
DR GeneReviews; MMAA; -.
DR HGNC; HGNC:18871; MMAA.
DR HPA; ENSG00000151611; Tissue enhanced (liver).
DR MalaCards; MMAA; -.
DR MIM; 251100; phenotype.
DR MIM; 607481; gene.
DR neXtProt; NX_Q8IVH4; -.
DR OpenTargets; ENSG00000151611; -.
DR Orphanet; 79310; Vitamin B12-responsive methylmalonic acidemia type cblA.
DR PharmGKB; PA134912808; -.
DR VEuPathDB; HostDB:ENSG00000151611; -.
DR eggNOG; ENOG502QR2W; Eukaryota.
DR GeneTree; ENSGT00390000009908; -.
DR HOGENOM; CLU_043725_2_2_1; -.
DR InParanoid; Q8IVH4; -.
DR OrthoDB; 817699at2759; -.
DR PhylomeDB; Q8IVH4; -.
DR TreeFam; TF313243; -.
DR PathwayCommons; Q8IVH4; -.
DR Reactome; R-HSA-3359475; Defective MMAA causes MMA, cblA type.
DR Reactome; R-HSA-3359478; Defective MUT causes MMAM.
DR Reactome; R-HSA-71032; Propionyl-CoA catabolism.
DR Reactome; R-HSA-9759218; Cobalamin (Cbl) metabolism.
DR SignaLink; Q8IVH4; -.
DR BioGRID-ORCS; 166785; 13 hits in 1071 CRISPR screens.
DR ChiTaRS; MMAA; human.
DR EvolutionaryTrace; Q8IVH4; -.
DR GeneWiki; MMAA; -.
DR GenomeRNAi; 166785; -.
DR Pharos; Q8IVH4; Tbio.
DR PRO; PR:Q8IVH4; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q8IVH4; protein.
DR Bgee; ENSG00000151611; Expressed in secondary oocyte and 176 other tissues.
DR ExpressionAtlas; Q8IVH4; baseline and differential.
DR Genevisible; Q8IVH4; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB.
DR GO; GO:0003924; F:GTPase activity; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0009235; P:cobalamin metabolic process; IDA:MGI.
DR Gene3D; 3.40.50.300; -; 1.
DR InterPro; IPR005129; GTPase_ArgK.
DR InterPro; IPR027417; P-loop_NTPase.
DR PANTHER; PTHR23408; PTHR23408; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00750; lao; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Chaperone; Cytoplasm; Disease variant; GTP-binding;
KW Hydrolase; Mitochondrion; Nucleotide-binding; Reference proteome;
KW Transit peptide.
FT TRANSIT 1..65
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 66..418
FT /note="Methylmalonic aciduria type A protein,
FT mitochondrial"
FT /id="PRO_0000002285"
FT BINDING 150..158
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000269|PubMed:20876572"
FT BINDING 292
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000269|PubMed:20876572,
FT ECO:0000269|PubMed:28497574"
FT BINDING 328..330
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000269|PubMed:20876572"
FT VARIANT 22..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:15523652,
FT ECO:0000269|PubMed:17957493"
FT /id="VAR_080004"
FT VARIANT 24..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080005"
FT VARIANT 54..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:15523652"
FT /id="VAR_080006"
FT VARIANT 68..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080007"
FT VARIANT 89
FT /note="L -> P (in MMAA; abolishes protein levels; decreases
FT protein stability; dbSNP:rs864309726)"
FT /evidence="ECO:0000269|PubMed:15523652,
FT ECO:0000269|PubMed:28497574"
FT /id="VAR_020835"
FT VARIANT 95..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080008"
FT VARIANT 98
FT /note="R -> G (in MMAA; decreases protein levels; no effect
FT on binding to GDP; decreases by 55% GTPase activity;
FT abolishes interaction with MUT; impairs GTPase activity
FT stimulation by MUT; highly reduces release of AdoCbl by
FT MMAB)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080009"
FT VARIANT 100..104
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080010"
FT VARIANT 120..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:17957493"
FT /id="VAR_080011"
FT VARIANT 129..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:15523652"
FT /id="VAR_080012"
FT VARIANT 133..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:17957493"
FT /id="VAR_080013"
FT VARIANT 145..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:15523652,
FT ECO:0000269|PubMed:17957493, ECO:0000269|PubMed:28497574"
FT /id="VAR_080014"
FT VARIANT 145
FT /note="R -> Q (in MMAA; highly decreases protein levels;
FT decreases protein stability; dbSNP:rs200577967)"
FT /evidence="ECO:0000269|PubMed:15523652,
FT ECO:0000269|PubMed:28497574"
FT /id="VAR_020836"
FT VARIANT 147
FT /note="G -> E (in MMAA; highly decreases protein levels;
FT decreases protein stability; no effect on binding to GDP;
FT no effect on GTPase activity; abolishes interaction with
FT MUT; impairs GTPase activity stimulation by MUT; highly
FT reduces release of AdoCbl by MMAB)"
FT /evidence="ECO:0000269|PubMed:15523652,
FT ECO:0000269|PubMed:28497574"
FT /id="VAR_080015"
FT VARIANT 188
FT /note="G -> R (in MMAA; decreases protein levels; no effect
FT on binding to GDP; no effect on GTPase activity; abolishes
FT interaction with MUT; impairs GTPase activity stimulation
FT by MUT; highly reduces release of AdoCbl by MMAB;
FT dbSNP:rs864309729)"
FT /evidence="ECO:0000269|PubMed:17957493,
FT ECO:0000269|PubMed:20876572, ECO:0000269|PubMed:28497574"
FT /id="VAR_080016"
FT VARIANT 192
FT /note="G -> D (in MMAA; no effect on protein levels; no
FT effect on binding to GDP; no effect on GTPase activity; no
FT effect on interaction with MUT; impairs GTPase activity
FT stimulation by MUT; reduces release of AdoCbl by MMAB;
FT dbSNP:rs1553958392)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080017"
FT VARIANT 196..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080018"
FT VARIANT 196
FT /note="R -> Q (in MMAA; unknown pathological significance;
FT decreases protein levels; no effect on binding to GDP; no
FT effect on GTPase activity; no effect on interaction with
FT MUT; impairs GTPase activity stimulation by MUT; reduces
FT release of AdoCbl by MMAB; dbSNP:rs144389160)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080019"
FT VARIANT 207
FT /note="Y -> C (in MMAA; decreases protein levels; no effect
FT on binding to GDP; no effect on GTPase activity; abolishes
FT interaction with MUT; impairs GTPase activity stimulation
FT by MUT; highly reduces release of AdoCbl by MMAB;
FT dbSNP:rs104893849)"
FT /evidence="ECO:0000269|PubMed:12438653,
FT ECO:0000269|PubMed:15523652, ECO:0000269|PubMed:28497574"
FT /id="VAR_017202"
FT VARIANT 209
FT /note="R -> S (in MMAA; decreases protein levels; no effect
FT on binding to GDP; no effect on GTPase activity; abolishes
FT interaction with MUT; impairs GTPase activity stimulation
FT by MUT; highly reduces release of AdoCbl by MMAB)"
FT /evidence="ECO:0000269|PubMed:23026888,
FT ECO:0000269|PubMed:28497574"
FT /id="VAR_071919"
FT VARIANT 218
FT /note="G -> E (in MMAA; decreases protein levels; no effect
FT on binding to GDP; no effect on GTPase activity; abolishes
FT interaction with MUT; impairs GTPase activity stimulation
FT by MUT; highly reduces release of AdoCbl by MMAB;
FT dbSNP:rs864309730)"
FT /evidence="ECO:0000269|PubMed:15523652,
FT ECO:0000269|PubMed:28497574"
FT /id="VAR_020837"
FT VARIANT 220
FT /note="V -> M (in MMAA; decreases protein levels; no effect
FT on binding to GDP; no effect on GTPase activity; abolishes
FT interaction with MUT; impairs GTPase activity stimulation
FT by MUT; highly reduces release of AdoCbl by MMAB;
FT dbSNP:rs150376474)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080020"
FT VARIANT 241
FT /note="I -> F (in MMAA; highly decreases protein levels;
FT decreases protein stability)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080021"
FT VARIANT 243
FT /note="T -> N (in MMAA; no effect on protein levels; no
FT effect on binding to GDP; no effect on GTPase activity;
FT abolishes interaction with MUT; impairs GTPase activity
FT stimulation by MUT; highly reduces release of AdoCbl by
FT MMAB; dbSNP:rs1553958417)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080022"
FT VARIANT 248..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:15523652,
FT ECO:0000269|PubMed:28497574"
FT /id="VAR_080023"
FT VARIANT 250
FT /note="E -> K (in MMAA; decreases protein levels; no effect
FT on binding to GDP; no effect on GTPase activity; no effect
FT on interaction with MUT; impairs GTPase activity
FT stimulation by MUT; reduces release of AdoCbl by MMAB)"
FT /evidence="ECO:0000269|PubMed:23026888,
FT ECO:0000269|PubMed:28497574"
FT /id="VAR_071920"
FT VARIANT 258
FT /note="D -> N (in MMAA; highly decreases protein levels)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080024"
FT VARIANT 274
FT /note="G -> D (in MMAA)"
FT /evidence="ECO:0000269|PubMed:23026888"
FT /id="VAR_071921"
FT VARIANT 274
FT /note="G -> S (in MMAA; decreases protein levels; no effect
FT on binding to GDP; no effect on GTPase activity; no effect
FT on interaction with MUT; impairs GTPase activity
FT stimulation by MUT; slightly reduces release of AdoCbl by
FT MMAB)"
FT /evidence="ECO:0000269|PubMed:23026888,
FT ECO:0000269|PubMed:28497574"
FT /id="VAR_071922"
FT VARIANT 276
FT /note="K -> E (in MMAA; decreases protein levels; no effect
FT on binding to GDP; no effect on GTPase activity; no effect
FT on interaction with MUT; impairs GTPase activity
FT stimulation by MUT; reduces release of AdoCbl by MMAB)"
FT /evidence="ECO:0000269|PubMed:23026888,
FT ECO:0000269|PubMed:28497574"
FT /id="VAR_071923"
FT VARIANT 287
FT /note="A -> D (in MMAA; highly decreases protein levels;
FT decreases protein stability; dbSNP:rs1553959024)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080025"
FT VARIANT 292
FT /note="D -> V (in MMAA; decreases protein levels; highly
FT decreases binding to GDP; no effect on GTPase activity;
FT abolishes interaction with MUT; impairs GTPase activity
FT stimulation by MUT; highly reduces release of AdoCbl by
FT MMAB; dbSNP:rs1553959025)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080026"
FT VARIANT 320..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:15523652"
FT /id="VAR_080027"
FT VARIANT 330..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:15523652,
FT ECO:0000269|PubMed:28497574"
FT /id="VAR_080028"
FT VARIANT 359..418
FT /note="Missing (in MMAA)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080029"
FT VARIANT 359
FT /note="R -> G (in MMAA; decreases protein levels; decreases
FT protein stability; no effect on binding to GDP; no effect
FT on GTPase activity; no effect on interaction with MUT;
FT impairs GTPase activity stimulation by MUT; reduces release
FT of AdoCbl by MMAB)"
FT /evidence="ECO:0000269|PubMed:15308131,
FT ECO:0000269|PubMed:28497574"
FT /id="VAR_038804"
FT VARIANT 359
FT /note="R -> Q (in MMAA; decreases protein levels;
FT dbSNP:rs864309731)"
FT /evidence="ECO:0000269|PubMed:15523652,
FT ECO:0000269|PubMed:23026888, ECO:0000269|PubMed:28497574"
FT /id="VAR_020838"
FT VARIANT 363
FT /note="Q -> H (in dbSNP:rs2270655)"
FT /evidence="ECO:0000269|PubMed:15523652"
FT /id="VAR_020423"
FT VARIANT 399
FT /note="G -> V (in MMAA; highly decreases protein levels;
FT decreases protein stability)"
FT /evidence="ECO:0000269|PubMed:28497574"
FT /id="VAR_080030"
FT MUTAGEN 290
FT /note="K->A: Abolishes binding to GTP and GTPase activity;
FT when associated with A-292."
FT /evidence="ECO:0000269|PubMed:28497574"
FT MUTAGEN 292
FT /note="D->A: Abolishes binding to GTP and GTPase activity;
FT when associated with A-290."
FT /evidence="ECO:0000269|PubMed:28497574"
FT HELIX 80..94
FT /evidence="ECO:0007829|PDB:2WWW"
FT HELIX 98..109
FT /evidence="ECO:0007829|PDB:2WWW"
FT HELIX 113..135
FT /evidence="ECO:0007829|PDB:2WWW"
FT TURN 136..139
FT /evidence="ECO:0007829|PDB:2WWW"
FT STRAND 144..149
FT /evidence="ECO:0007829|PDB:2WWW"
FT HELIX 156..169
FT /evidence="ECO:0007829|PDB:2WWW"
FT STRAND 174..178
FT /evidence="ECO:0007829|PDB:2WWW"
FT STRAND 206..209
FT /evidence="ECO:0007829|PDB:2WWW"
FT HELIX 224..233
FT /evidence="ECO:0007829|PDB:2WWW"
FT STRAND 237..242
FT /evidence="ECO:0007829|PDB:2WWW"
FT HELIX 250..254
FT /evidence="ECO:0007829|PDB:2WWW"
FT STRAND 258..264
FT /evidence="ECO:0007829|PDB:2WWW"
FT STRAND 284..288
FT /evidence="ECO:0007829|PDB:2WWW"
FT HELIX 293..295
FT /evidence="ECO:0007829|PDB:2WWW"
FT HELIX 296..310
FT /evidence="ECO:0007829|PDB:2WWW"
FT STRAND 323..326
FT /evidence="ECO:0007829|PDB:2WWW"
FT TURN 329..331
FT /evidence="ECO:0007829|PDB:2WWW"
FT HELIX 335..352
FT /evidence="ECO:0007829|PDB:2WWW"
FT HELIX 354..381
FT /evidence="ECO:0007829|PDB:2WWW"
FT HELIX 383..397
FT /evidence="ECO:0007829|PDB:2WWW"
FT HELIX 403..415
FT /evidence="ECO:0007829|PDB:2WWW"
SQ SEQUENCE 418 AA; 46538 MW; AD9EA19DDB8DEEF8 CRC64;
MPMLLPHPHQ HFLKGLLRAP FRCYHFIFHS STHLGSGIPC AQPFNSLGLH CTKWMLLSDG
LKRKLCVQTT LKDHTEGLSD KEQRFVDKLY TGLIQGQRAC LAEAITLVES THSRKKELAQ
VLLQKVLLYH REQEQSNKGK PLAFRVGLSG PPGAGKSTFI EYFGKMLTER GHKLSVLAVD
PSSCTSGGSL LGDKTRMTEL SRDMNAYIRP SPTRGTLGGV TRTTNEAILL CEGAGYDIIL
IETVGVGQSE FAVADMVDMF VLLLPPAGGD ELQGIKRGII EMADLVAVTK SDGDLIVPAR
RIQAEYVSAL KLLRKRSQVW KPKVIRISAR SGEGISEMWD KMKDFQDLML ASGELTAKRR
KQQKVWMWNL IQESVLEHFR THPTVREQIP LLEQKVLIGA LSPGLAADFL LKAFKSRD
