MA2A1_HUMAN
ID MA2A1_HUMAN Reviewed; 1144 AA.
AC Q16706; Q16767;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2007, sequence version 2.
DT 03-AUG-2022, entry version 190.
DE RecName: Full=Alpha-mannosidase 2;
DE EC=3.2.1.114 {ECO:0000250|UniProtKB:P28494};
DE AltName: Full=Golgi alpha-mannosidase II;
DE Short=AMan II;
DE Short=Man II;
DE AltName: Full=Mannosidase alpha class 2A member 1;
DE AltName: Full=Mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase;
GN Name=MAN2A1; Synonyms=MANA2;
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].
RC TISSUE=Liver;
RX PubMed=8524845; DOI=10.1073/pnas.92.25.11766;
RA Misago M., Liao Y.-F., Kudo S., Eto S., Mattei M.-G., Moremen K.W.,
RA Fukuda M.N.;
RT "Molecular cloning and expression of cDNAs encoding human alpha-mannosidase
RT II and a previously unrecognized alpha-mannosidase IIx isozyme.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:11766-11770(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RA Misumi Y., Hashimoto C., Sohoda M., Ogata S., Ikehara Y.;
RT "Molecular cloning and sequence analysis of human Golgi mannosidase II.";
RL Submitted (SEP-1995) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-78 AND ASN-1125.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-80 AND SER-82, AND
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 [6]
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 [7]
RP VARIANT VAL-1012.
RX PubMed=25787250; DOI=10.1073/pnas.1503696112;
RA Cromer M.K., Choi M., Nelson-Williams C., Fonseca A.L., Kunstman J.W.,
RA Korah R.M., Overton J.D., Mane S., Kenney B., Malchoff C.D., Stalberg P.,
RA Akerstroem G., Westin G., Hellman P., Carling T., Bjoerklund P.,
RA Lifton R.P.;
RT "Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in
RT insulin-producing adenomas.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:4062-4067(2015).
CC -!- FUNCTION: Catalyzes the first committed step in the biosynthesis of
CC complex N-glycans. It controls conversion of high mannose to complex N-
CC glycans; the final hydrolytic step in the N-glycan maturation pathway.
CC {ECO:0000250|UniProtKB:P28494}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 H2O + N(4)-{beta-D-GlcNAc-(1->2)-alpha-D-Man-(1->3)-[alpha-
CC D-Man-(1->3)-[alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-
CC (1->4)-beta-D-GlcNAc-(1->4)-beta-D-GlcNAc}-L-asparaginyl-[protein] =
CC 2 alpha-D-mannopyranose + N(4)-{beta-D-GlcNAc-(1->2)-alpha-D-Man-
CC (1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-
CC beta-D-GlcNAc}-L-asparaginyl-[protein]; Xref=Rhea:RHEA:56052,
CC Rhea:RHEA-COMP:14368, Rhea:RHEA-COMP:14369, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:28729, ChEBI:CHEBI:60615, ChEBI:CHEBI:60625;
CC EC=3.2.1.114; Evidence={ECO:0000250|UniProtKB:P28494};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:Q29451};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:Q29451};
CC -!- PATHWAY: Protein modification; protein glycosylation.
CC -!- SUBUNIT: Homodimer; disulfide-linked. {ECO:0000250|UniProtKB:P28494}.
CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane
CC {ECO:0000250|UniProtKB:P28494}; Single-pass type II membrane protein
CC {ECO:0000250|UniProtKB:P28494}.
CC -!- PTM: Glycosylated. {ECO:0000269|PubMed:16335952}.
CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 38 family. {ECO:0000305}.
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DR EMBL; U31520; AAC50302.1; -; mRNA.
DR EMBL; D63998; BAA10017.1; -; mRNA.
DR CCDS; CCDS34209.1; -.
DR RefSeq; NP_002363.2; NM_002372.3.
DR AlphaFoldDB; Q16706; -.
DR SMR; Q16706; -.
DR BioGRID; 110297; 108.
DR IntAct; Q16706; 10.
DR MINT; Q16706; -.
DR STRING; 9606.ENSP00000261483; -.
DR BindingDB; Q16706; -.
DR ChEMBL; CHEMBL4056; -.
DR DrugBank; DB06984; (1R,2R,3R,4S,5R)-4-(Benzylamino)-5-(methylthio)cyclopentane-1,2,3-triol.
DR DrugBank; DB08321; (1S,2S,3R,6R)-4-(hydroxymethyl)-6-(octylamino)cyclohex-4-ene-1,2,3-triol.
DR DrugBank; DB03955; 1-deoxymannojirimycin.
DR DrugBank; DB02318; 2-deoxy-2-fluoro-alpha-D-mannosyl fluoride.
DR DrugBank; DB03008; 5-fluoro-beta-L-gulosyl fluoride.
DR DrugBank; DB03414; 5-Thio-a/B-D-Mannopyranosylamine.
DR DrugBank; DB02492; Ghavamiol.
DR DrugBank; DB02742; Kifunensine.
DR DrugBank; DB02034; Tridolgosir.
DR CAZy; GH38; Glycoside Hydrolase Family 38.
DR GlyConnect; 1917; 9 N-Linked glycans (1 site).
DR GlyGen; Q16706; 3 sites, 9 N-linked glycans (1 site).
DR iPTMnet; Q16706; -.
DR PhosphoSitePlus; Q16706; -.
DR BioMuta; MAN2A1; -.
DR DMDM; 146345453; -.
DR EPD; Q16706; -.
DR jPOST; Q16706; -.
DR MassIVE; Q16706; -.
DR MaxQB; Q16706; -.
DR PaxDb; Q16706; -.
DR PeptideAtlas; Q16706; -.
DR PRIDE; Q16706; -.
DR ProteomicsDB; 61038; -.
DR Antibodypedia; 13482; 190 antibodies from 30 providers.
DR DNASU; 4124; -.
DR Ensembl; ENST00000261483.5; ENSP00000261483.4; ENSG00000112893.10.
DR GeneID; 4124; -.
DR KEGG; hsa:4124; -.
DR MANE-Select; ENST00000261483.5; ENSP00000261483.4; NM_002372.4; NP_002363.2.
DR UCSC; uc003kou.3; human.
DR CTD; 4124; -.
DR DisGeNET; 4124; -.
DR GeneCards; MAN2A1; -.
DR HGNC; HGNC:6824; MAN2A1.
DR HPA; ENSG00000112893; Tissue enhanced (brain).
DR MIM; 154582; gene.
DR neXtProt; NX_Q16706; -.
DR OpenTargets; ENSG00000112893; -.
DR PharmGKB; PA30573; -.
DR VEuPathDB; HostDB:ENSG00000112893; -.
DR eggNOG; KOG1958; Eukaryota.
DR GeneTree; ENSGT01030000234638; -.
DR HOGENOM; CLU_004690_1_0_1; -.
DR InParanoid; Q16706; -.
DR OMA; HHEVNVQ; -.
DR OrthoDB; 1101882at2759; -.
DR PhylomeDB; Q16706; -.
DR TreeFam; TF313152; -.
DR BioCyc; MetaCyc:HS03629-MON; -.
DR PathwayCommons; Q16706; -.
DR Reactome; R-HSA-6811438; Intra-Golgi traffic.
DR Reactome; R-HSA-9694548; Maturation of spike protein.
DR Reactome; R-HSA-975578; Reactions specific to the complex N-glycan synthesis pathway.
DR SignaLink; Q16706; -.
DR UniPathway; UPA00378; -.
DR BioGRID-ORCS; 4124; 11 hits in 1081 CRISPR screens.
DR ChiTaRS; MAN2A1; human.
DR GeneWiki; MAN2A1; -.
DR GenomeRNAi; 4124; -.
DR Pharos; Q16706; Tbio.
DR PRO; PR:Q16706; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q16706; protein.
DR Bgee; ENSG00000112893; Expressed in corpus callosum and 205 other tissues.
DR Genevisible; Q16706; HS.
DR GO; GO:0005801; C:cis-Golgi network; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005797; C:Golgi medial cisterna; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0004559; F:alpha-mannosidase activity; IBA:GO_Central.
DR GO; GO:0030246; F:carbohydrate binding; IEA:InterPro.
DR GO; GO:0016799; F:hydrolase activity, hydrolyzing N-glycosyl compounds; IEA:Ensembl.
DR GO; GO:0004572; F:mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase activity; TAS:ProtInc.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0042803; F:protein homodimerization activity; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0048286; P:lung alveolus development; IEA:Ensembl.
DR GO; GO:0006013; P:mannose metabolic process; IEA:InterPro.
DR GO; GO:0007005; P:mitochondrion organization; IEA:Ensembl.
DR GO; GO:0006491; P:N-glycan processing; IBA:GO_Central.
DR GO; GO:0050769; P:positive regulation of neurogenesis; IEA:Ensembl.
DR GO; GO:0006517; P:protein deglycosylation; IBA:GO_Central.
DR GO; GO:0006486; P:protein glycosylation; IEA:UniProtKB-UniPathway.
DR GO; GO:0007585; P:respiratory gaseous exchange by respiratory system; IEA:Ensembl.
DR GO; GO:0060042; P:retina morphogenesis in camera-type eye; IEA:Ensembl.
DR GO; GO:0007033; P:vacuole organization; IEA:Ensembl.
DR GO; GO:0019082; P:viral protein processing; TAS:Reactome.
DR Gene3D; 1.20.1270.50; -; 1.
DR Gene3D; 2.60.40.1180; -; 1.
DR Gene3D; 3.20.110.10; -; 1.
DR InterPro; IPR011013; Gal_mutarotase_sf_dom.
DR InterPro; IPR011330; Glyco_hydro/deAcase_b/a-brl.
DR InterPro; IPR011682; Glyco_hydro_38_C.
DR InterPro; IPR015341; Glyco_hydro_38_cen.
DR InterPro; IPR037094; Glyco_hydro_38_cen_sf.
DR InterPro; IPR000602; Glyco_hydro_38_N.
DR InterPro; IPR027291; Glyco_hydro_38_N_sf.
DR InterPro; IPR028995; Glyco_hydro_57/38_cen_sf.
DR InterPro; IPR013780; Glyco_hydro_b.
DR Pfam; PF09261; Alpha-mann_mid; 1.
DR Pfam; PF07748; Glyco_hydro_38C; 1.
DR Pfam; PF01074; Glyco_hydro_38N; 1.
DR SMART; SM00872; Alpha-mann_mid; 1.
DR SUPFAM; SSF74650; SSF74650; 1.
DR SUPFAM; SSF88688; SSF88688; 1.
DR SUPFAM; SSF88713; SSF88713; 1.
PE 1: Evidence at protein level;
KW Disulfide bond; Glycoprotein; Glycosidase; Golgi apparatus; Hydrolase;
KW Membrane; Metal-binding; Phosphoprotein; Reference proteome; Signal-anchor;
KW Transmembrane; Transmembrane helix; Zinc.
FT CHAIN 1..1144
FT /note="Alpha-mannosidase 2"
FT /id="PRO_0000206902"
FT TOPO_DOM 1..5
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 6..26
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 27..1144
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT ACT_SITE 289
FT /note="Nucleophile"
FT /evidence="ECO:0000250"
FT BINDING 175
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 177
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 289
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 569
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT MOD_RES 80
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 82
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT CARBOHYD 78
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952"
FT CARBOHYD 93
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 1125
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952"
FT VARIANT 1012
FT /note="L -> V"
FT /evidence="ECO:0000269|PubMed:25787250"
FT /id="VAR_074182"
FT CONFLICT 608
FT /note="L -> G (in Ref. 1; AAC50302)"
FT /evidence="ECO:0000305"
FT CONFLICT 1026
FT /note="Missing (in Ref. 2; BAA10017)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1144 AA; 131141 MW; A1814C63D1CE4FAC CRC64;
MKLSRQFTVF GSAIFCVVIF SLYLMLDRGH LDYPRNPRRE GSFPQGQLSM LQEKIDHLER
LLAENNEIIS NIRDSVINLS ESVEDGPKSS QSNFSQGAGS HLLPSQLSLS VDTADCLFAS
QSGSHNSDVQ MLDVYSLISF DNPDGGVWKQ GFDITYESNE WDTEPLQVFV VPHSHNDPGW
LKTFNDYFRD KTQYIFNNMV LKLKEDSRRK FIWSEISYLS KWWDIIDIQK KDAVKSLIEN
GQLEIVTGGW VMPDEATPHY FALIDQLIEG HQWLENNIGV KPRSGWAIDP FGHSPTMAYL
LNRAGLSHML IQRVHYAVKK HFALHKTLEF FWRQNWDLGS VTDILCHMMP FYSYDIPHTC
GPDPKICCQF DFKRLPGGRF GCPWGVPPET IHPGNVQSRA RMLLDQYRKK SKLFRTKVLL
APLGDDFRYC EYTEWDLQFK NYQQLFDYMN SQSKFKVKIQ FGTLSDFFDA LDKADETQRD
KGQSMFPVLS GDFFTYADRD DHYWSGYFTS RPFYKRMDRI MESHLRAAEI LYYFALRQAH
KYKINKFLSS SLYTALTEAR RNLGLFQHHD AITGTAKDWV VVDYGTRLFH SLMVLEKIIG
NSAFLLILKD KLTYDSYSPD TFLEMDLKQK SQDSLPQKNI IRLSAEPRYL VVYNPLEQDR
ISLVSVYVSS PTVQVFSASG KPVEVQVSAV WDTANTISET AYEISFRAHI PPLGLKVYKI
LESASSNSHL ADYVLYKNKV EDSGIFTIKN MINTEEGITL ENSFVLLRFD QTGLMKQMMT
KEDGKHHEVN VQFSWYGTTI KRDKSGAYLF LPDGNAKPYV YTTPPFVRVT HGRIYSEVTC
FFDHVTHRVR LYHIQGIEGQ SVEVSNIVDI RKVYNREIAM KISSDIKSQN RFYTDLNGYQ
IQPRMTLSKL PLQANVYPMT TMAYIQDAKH RLTLLSAQSL GVSSLNSGQI EVIMDRRLMQ
DDNRGLEQGI QDNKITANLF RILLEKRSAV NTEEEKKSVS YPSLLSHITS SLMNHPVIPM
ANKFSSPTLE LQGEFSPLQS SLPCDIHLVN LRTIQSKVGN GHSNEAALIL HRKGFDCRFS
SKGTGLFCST TQGKILVQKL LNKFIVESLT PSSLSLMHSP PGTQNISEIN LSPMEISTFR
IQLR
