Q9UKM7 (MA1B1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase
EC=3.2.1.113

Alternative name(s):
ER alpha-1,2-mannosidase
ER mannosidase 1
Short name=ERMan1
Man9GlcNAc2-specific-processing alpha-mannosidase
Mannosidase alpha class 1B member 1

Gene names

Name:	MAN1B1
ORF Names:	UNQ747/PRO1477

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	699 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Involved in glycoprotein quality control targeting of misfolded glycoproteins for degradation. It primarily trims a single alpha-1,2-linked mannose residue from Man9GlcNAc2 to produce Man8GlcNAc2, but at high enzyme concentrations, as found in the ER quality control compartment (ERQC), it further trims the carbohydrates to Man5-6GlcNAc2. Ref.6 Ref.7
Catalytic activity	Hydrolysis of the terminal (1->2)-linked alpha-D-mannose residues in the oligo-mannose oligosaccharide Man9(GlcNAc)2. Ref.2 Ref.6 Ref.9
Cofactor	Calcium.
Enzyme regulation	Inhibited by both 1-deoxymannojirimycin (dMNJ) and kifunensine. Ref.2
Pathway	Protein modification; protein glycosylation.
Subcellular location	Endoplasmic reticulum membrane; Single-pass type II membrane protein Ref.2.
Tissue specificity	Widely expressed. Ref.1 Ref.2
Involvement in disease	Mental retardation, autosomal recessive 15 (MRT15) [MIM:614202]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10
Sequence similarities	Belongs to the glycosyl hydrolase 47 family.
Caution	It is uncertain whether Met-1 or Met-37 is the initiator.
Biophysicochemical properties	Kinetic parameters: KM=0.4 mM for Man9GlcNAc2 Ref.1 pH dependence: Optimum pH is between 6.5 and 6.9.

Ontologies

Keywords
Cellular component	Endoplasmic reticulum Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation Mental retardation
Domain	Signal-anchor Transmembrane Transmembrane helix
Ligand	Calcium
Molecular function	Glycosidase Hydrolase
PTM	Disulfide bond
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	ER-associated protein catabolic process Inferred from mutant phenotype Ref.7. Source: UniProtKB oligosaccharide metabolic process Traceable author statement Ref.2. Source: ProtInc post-translational protein modification Traceable author statement. Source: Reactome protein N-linked glycosylation via asparagine Traceable author statement. Source: Reactome protein folding Traceable author statement. Source: Reactome
Cellular_component	endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell endoplasmic reticulum quality control compartment Traceable author statement. Source: Reactome integral to membrane Traceable author statement Ref.1. Source: UniProtKB
Molecular_function	calcium ion binding Traceable author statement Ref.1. Source: UniProtKB mannosyl-oligosaccharide 1,2-alpha-mannosidase activity Inferred from direct assay Ref.6. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 699

699

Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase

PRO_0000210314

Regions

Topological domain

1 – 84

84

Cytoplasmic Potential

Transmembrane

85 – 105

21

Helical; Signal-anchor for type II membrane protein; Potential

Topological domain

106 – 699

594

Lumenal Potential

Compositional bias

39 – 45

7

Poly-Pro

Sites

Active site

330

1

Proton donor Probable

Active site

463

1

Probable

Active site

599

1

Probable

Amino acid modifications

Disulfide bond

527 ↔ 556

Ref.8

Natural variations

Natural variant

59

1

N → S. Ref.1 Ref.2 Ref.3 Ref.5
Corresponds to variant rs968733 [ dbSNP | Ensembl ].

VAR_055841

Natural variant

334

1

R → C in MRT15; results in about 1300-fold decrease in activity. Ref.10

VAR_066592

Natural variant

397

1

E → K in MRT15; disrupts stable protein expression. Ref.10

VAR_066593

Experimental info

Mutagenesis

330

1

E → Q: About 44-fold reduction in K(cat), slight reduction in K(m), about 100-fold increase in binding affinity for Man(9)GlcnAc(2) but no change in binding affinity for the inhibitor, dMNJ. Even further greater reduction in K(cat) and increase in K(m); when associated with Q-599. Ref.9

Mutagenesis

463

1

D → N: Some reduction in K(cat) but no change in K(m), abolishes almost all binding to Man(9)GlcnAc(2) but reduced binding to the inhibitor dMNJ by about 73-fold. Further reduction in K(m) but slight increase in K(m); when associated with Q-599. Ref.9

Mutagenesis

524

1

H → A: About 4-fold reduction in K(cat). Ref.9

Mutagenesis

599

1

E → Q: Very significant reduction in K(cat), 4-fold weaker binding affinity for Man(9)GlcnAc(2) but about 1000-fold reduction in binding affinity for the inhibitor, dMNJ. Significant reductions in K(cat) and slight increase in K(m); when associated with E-330 or N-463. Ref.9

Sequence conflict

204

1

T → A in AAD45504. Ref.2

Sequence conflict

223

1

S → P in AAD45504. Ref.2

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

699

Helix Strand Turn

Details...

Beta strand

244 – 246

3

Helix

248 – 267

20

Beta strand

271 – 275

5

Turn

276 – 279

4

Beta strand

280 – 282

3

Beta strand

284 – 287

4

Helix

289 – 300

12

Helix

304 – 317

14

Beta strand

325 – 327

3

Helix

328 – 346

19

Helix

349 – 362

14

Helix

363 – 366

4

Beta strand

368 – 370

3

Beta strand

375 – 378

4

Turn

379 – 381

3

Beta strand

391 – 394

4

Helix

395 – 399

5

Helix

402 – 412

11

Helix

416 – 429

14

Beta strand

441 – 444

4

Turn

445 – 447

3

Beta strand

450 – 452

3

Turn

460 – 462

3

Helix

463 – 475

13

Helix

481 – 497

17

Beta strand

499 – 501

3

Turn

503 – 505

3

Beta strand

508 – 510

3

Beta strand

512 – 514

3

Beta strand

517 – 519

3

Beta strand

521 – 523

3

Helix

524 – 527

4

Helix

528 – 538

11

Helix

543 – 561

19

Beta strand

563 – 566

4

Beta strand

570 – 573

4

Beta strand

584 – 586

3

Helix

589 – 591

3

Helix

599 – 611

13

Helix

615 – 630

16

Helix

659 – 662

4

Helix

664 – 672

9

Turn

676 – 679

4

Turn

681 – 683

3

Beta strand

684 – 686

3

Beta strand

692 – 694

3

Sequences

	Sequence		Length	Mass (Da)
	Q9UKM7 [UniParc]. Last modified March 7, 2006. Version 2. Checksum: B8BF3BE333D90261	FASTA	699	79,580
	10 20 30 40 50 60 MAACEGRRSG ALGSSQSDFL TPPVGGAPWA VATTVVMYPP PPPPPHRDFI SVTLSFGENY 70 80 90 100 110 120 DNSKSWRRRS CWRKWKQLSR LQRNMILFLL AFLLFCGLLF YINLADHWKA LAFRLEEEQK 130 140 150 160 170 180 MRPEIAGLKP ANPPVLPAPQ KADTDPENLP EISSQKTQRH IQRGPPHLQI RPPSQDLKDG 190 200 210 220 230 240 TQEEATKRQE APVDPRPEGD PQRTVISWRG AVIEPEQGTE LPSRRAEVPT KPPLPPARTQ 250 260 270 280 290 300 GTPVHLNYRQ KGVIDVFLHA WKGYRKFAWG HDELKPVSRS FSEWFGLGLT LIDALDTMWI 310 320 330 340 350 360 LGLRKEFEEA RKWVSKKLHF EKDVDVNLFE STIRILGGLL SAYHLSGDSL FLRKAEDFGN 370 380 390 400 410 420 RLMPAFRTPS KIPYSDVNIG TGVAHPPRWT SDSTVAEVTS IQLEFRELSR LTGDKKFQEA 430 440 450 460 470 480 VEKVTQHIHG LSGKKDGLVP MFINTHSGLF THLGVFTLGA RADSYYEYLL KQWIQGGKQE 490 500 510 520 530 540 TQLLEDYVEA IEGVRTHLLR HSEPSKLTFV GELAHGRFSA KMDHLVCFLP GTLALGVYHG 550 560 570 580 590 600 LPASHMELAQ ELMETCYQMN RQMETGLSPE IVHFNLYPQP GRRDVEVKPA DRHNLLRPET 610 620 630 640 650 660 VESLFYLYRV TGDRKYQDWG WEILQSFSRF TRVPSGGYSS INNVQDPQKP EPRDKMESFF 670 680 690 LGETLKYLFL LFSDDPNLLS LDAYVFNTEA HPLPIWTPA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and expression of a specific human alpha1,2-mannosidase that trims Man9GlcNAc2 to Man8GlcNAc2 isomer B during N-glycan biosynthesis." Tremblay L.O., Herscovics A. Glycobiology 9:1073-1078(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], BIOPHYSICOCHEMICAL PROPERTIES, TISSUE SPECIFICITY, VARIANT SER-59. Tissue: Fetal brain, Liver, Placenta and Testis.
[2]	"Identification, expression, and characterization of a cDNA encoding human endoplasmic reticulum mannosidase I, the enzyme that catalyzes the first mannose trimming step in mammalian Asn-linked oligosaccharide biosynthesis." Gonzalez D.S., Karaveg K., Vandersall-Nairn A.S., Lal A., Moremen K.W. J. Biol. Chem. 274:21375-21386(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 37-699, TISSUE SPECIFICITY, ENZYME ACTIVITY, ENZYME REGULATION, SUBCELLULAR LOCATION, VARIANT SER-59.
[3]	"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment." Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M. Genome Res. 13:2265-2270(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT SER-59.
[4]	"DNA sequence and analysis of human chromosome 9." Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., Bagguley C.L. , Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., Dunham I. Nature 429:369-374(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT SER-59. Tissue: Lung and Placenta.
[6]	"The specificity of the yeast and human class I ER alpha 1,2-mannosidases involved in ER quality control is not as strict previously reported." Herscovics A., Romero P.A., Tremblay L.O. Glycobiology 12:14G-15G(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY.
[7]	"Endoplasmic reticulum (ER) mannosidase I is compartmentalized and required for N-glycan trimming to Man5-6GlcNAc2 in glycoprotein ER-associated degradation." Avezov E., Frenkel Z., Ehrlich M., Herscovics A., Lederkremer G.Z. Mol. Biol. Cell 19:216-225(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[8]	"Structural basis for catalysis and inhibition of N-glycan processing class I alpha 1,2-mannosidases." Vallee F., Karaveg K., Herscovics A., Moremen K.W., Howell P.L. J. Biol. Chem. 275:41287-41298(2000) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 243-699, DISULFIDE BOND.
[9]	"Mechanism of class 1 (glycosylhydrolase family 47) {alpha}-mannosidases involved in N-glycan processing and endoplasmic reticulum quality control." Karaveg K., Siriwardena A., Tempel W., Liu Z.J., Glushka J., Wang B.C., Moremen K.W. J. Biol. Chem. 280:16197-16207(2005) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.41 ANGSTROMS) OF 172-699 IN COMPLEX WITH A THIO-DISACCHARIDE SUBSTRATE ANALOG, ENZYME ACTIVITY, MUTAGENESIS OF GLU-330; ASP-463; HIS-524 AND GLU-599.
[10]	"Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability." Rafiq M.A., Kuss A.W., Puettmann L., Noor A., Ramiah A., Ali G., Hu H., Kerio N.A., Xiang Y., Garshasbi M., Khan M.A., Ishak G.E., Weksberg R., Ullmann R., Tzschach A., Kahrizi K., Mahmood K., Naeem F. , Ayub M., Moremen K.W., Vincent J.B., Ropers H.H., Ansar M., Najmabadi H. Am. J. Hum. Genet. 89:176-182(2011) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS MRT15 CYS-334 AND LYS-397, CHARACTERIZATION OF VARIANTS MRT15 CYS-334 AND LYS-397.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF148509 mRNA. Translation: AAF03215.1.
AF145732 mRNA. Translation: AAD45504.1.
AY358465 mRNA. Translation: AAQ88830.1.
AL929554, AL807752 Genomic DNA. Translation: CAH72887.1.
AL807752, AL929554 Genomic DNA. Translation: CAI12781.1.
BC002953 mRNA. Translation: AAH02953.1.
BC006079 mRNA. Translation: AAH06079.1.

IPI

IPI00008207.

RefSeq

NP_057303.2. NM_016219.4.

UniGene

Hs.279881.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1FMI	X-ray	1.90	A	243-697	[»]
1FO2	X-ray	2.38	A	243-699	[»]
1FO3	X-ray	1.75	A	243-699	[»]
1X9D	X-ray	1.41	A	172-699	[»]

ProteinModelPortal

Q9UKM7.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9UKM7. 1 interaction.

STRING

9606.ENSP00000360645.

Protein family/group databases

CAZy

GH47. Glycoside Hydrolase Family 47.

PTM databases

PhosphoSite

Q9UKM7.

Polymorphism databases

DMDM

93195043.

Proteomic databases

PaxDb

Q9UKM7.

PRIDE

Q9UKM7.

Protocols and materials databases

DNASU

11253.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000371589; ENSP00000360645; ENSG00000177239.

GeneID

11253.

KEGG

hsa:11253.

UCSC

uc004cld.2. human.

Organism-specific databases

CTD

11253.

GeneCards

GC09P139981.

H-InvDB

HIX0035043.

HGNC

HGNC:6823. MAN1B1.

HPA

HPA051516.

MIM

604346. gene.
614202. phenotype.

neXtProt

NX_Q9UKM7.

Orphanet

88616. Autosomal recessive nonsyndromic intellectual deficit.

PharmGKB

PA30572.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG300315.

HOGENOM

HOG000181987.

HOVERGEN

HBG052389.

KO

K01230.

OMA

HFNLHAQ.

OrthoDB

EOG4J9MZB.

PhylomeDB

Q9UKM7.

Enzyme and pathway databases

BRENDA

3.2.1.113. 2681.

Reactome

REACT_17015. Metabolism of proteins.

UniPathway

UPA00378.

Gene expression databases

ArrayExpress

Q9UKM7.

Bgee

Q9UKM7.

CleanEx

HS_MAN1B1.

Genevestigator

Q9UKM7.

GermOnline

ENSG00000177239. Homo sapiens.

Family and domain databases

Gene3D

1.50.10.50. 1 hit.

InterPro

IPR001382. Glyco_hydro_47.
[Graphical view]

PANTHER

PTHR11742. PTHR11742. 1 hit.

Pfam

PF01532. Glyco_hydro_47. 1 hit.
[Graphical view]

PRINTS

PR00747. GLYHDRLASE47.

SUPFAM

SSF48225. Glyco_hydro_47. 1 hit.

ProtoNet

Search...

Other

BindingDB

Q9UKM7.

ChEMBL

CHEMBL2308.

EvolutionaryTrace

Q9UKM7.

GenomeRNAi

11253.

NextBio

42822.

SOURCE

Search...

Entry information

Entry name

MA1B1_HUMAN

Accession

Primary (citable) accession number: Q9UKM7
Secondary accession number(s): Q5VSG3, Q9BRS9, Q9Y5K7

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 16, 2001
Last sequence update:	March 7, 2006
Last modified:	May 1, 2013
This is version 127 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.