Reviewed, UniProtKB/Swiss-Prot P36894 (BMR1A_HUMAN)

Names and origin

Protein names

Recommended name:
    Bone morphogenetic protein receptor type-1A
    EC=2.7.11.30
Alternative name(s):
    Serine/threonine-protein kinase receptor R5
      Short name=SKR5
    Activin receptor-like kinase 3
      Short name=ALK-3
    CD_antigen=CD292

Gene names

Name:	BMPR1A
Synonyms:	ACVRLK3, ALK3

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	532 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for BMP-2 and BMP-4.
Catalytic activity	ATP + [receptor-protein] = ADP + [receptor-protein] phosphate.
Cofactor	Magnesium or manganese By similarity.
Subcellular location	Membrane; Single-pass type I membrane protein.
Tissue specificity	Highly expressed in skeletal muscle.
Involvement in disease	Defects in BMPR1A are a cause of juvenile polyposis syndrome (JPS) [MIM:174900]; also known as juvenile intestinal polyposis (JIP). JPS is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers. Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Defects in BMPR1A are a cause of Cowden disease (CD) [MIM:158350]. CD is an autosomal dominant cancer syndrome characterized by multiple hamartomas and by a high risk for breast, thyroid and endometrial cancers. Ref.5 Ref.6 Defects in BMPR1A are the cause of hereditary mixed polyposis syndrome 2 (HMPS2) [MIM:610069]. Hereditary mixed polyposis syndrome (HMPS) is characterized by atypical juvenile polyps, colonic adenomas, and colorectal carcinomas. Ref.5 A microdeletion of chromosome 10q23 involving BMPR1A and PTEN is a cause of chromosome 10q23 deletion syndrome [MIM:612242]. This syndrome shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome. The 10q23 microdeletion is also found in patients manifesting juvenile polyposis of infancy without cognitive disability. Juvenile polyposis of infancy is characterized by the appearance of extensive gastrointestinal juvenile hamartomatous polyposis in the first months of life. Ref.5
Sequence similarities	Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily. Contains 1 GS domain. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Signal Transmembrane
Ligand	ATP-binding Magnesium Manganese Metal-binding Nucleotide-binding
Molecular function	Kinase Receptor Serine/threonine-protein kinase Transferase
PTM	Disulfide bond Glycoprotein Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	BMP signaling pathway Inferred from direct assay. Source: UniProtKB immune response Inferred from mutant phenotype. Source: UniProtKB positive regulation of SMAD protein nuclear translocation Inferred from direct assay. Source: UniProtKB positive regulation of bone mineralization Inferred from mutant phenotype. Source: UniProtKB positive regulation of osteoblast differentiation Inferred from mutant phenotype. Source: UniProtKB positive regulation of pathway-restricted SMAD protein phosphorylation Inferred from direct assay. Source: UniProtKB protein amino acid phosphorylation Inferred from direct assay. Source: HGNC
Cellular component	integral to membrane Ref.1 Traceable author statement. Source: ProtInc plasma membrane Inferred from Experiment. Source: Reactome
Molecular function	ATP binding Inferred from direct assay. Source: HGNC SMAD binding Inferred from direct assay. Source: HGNC magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW manganese ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein homodimerization activity Inferred from direct assay. Source: UniProtKB transforming growth factor beta receptor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 23

23

Potential

Chain

24 – 532

509

Bone morphogenetic protein receptor type-1A

PRO_0000024410

Regions

Topological domain

24 – 152

129

Extracellular Potential

Transmembrane

153 – 176

24

Potential

Topological domain

177 – 532

356

Cytoplasmic Potential

Domain

204 – 233

30

GS

Domain

234 – 525

292

Protein kinase

Nucleotide binding

240 – 248

9

ATP By similarity

Sites

Active site

362

1

Proton acceptor By similarity

Binding site

261

1

ATP By similarity

Amino acid modifications

Modified residue

215

1

Phosphoserine Ref.3

Modified residue

216

1

Phosphoserine Ref.3

Modified residue

218

1

Phosphoserine Ref.3

Modified residue

220

1

Phosphoserine Ref.3

Glycosylation

73

1

N-linked (GlcNAc...) Potential

Disulfide bond

61 ↔ 82

Disulfide bond

63 ↔ 67

Disulfide bond

76 ↔ 100

Disulfide bond

110 ↔ 124

Disulfide bond

125 ↔ 130

Natural variations

Natural variant

2

1

P → T Ref.1 Ref.12

VAR_041397

Natural variant

58

1

F → Y in a renal clear cell carcinoma sample; somatic mutation. Ref.12

VAR_041398

Natural variant

62

1

Y → D in JPS. Ref.7

VAR_022828

Natural variant

82

1

C → Y in JPS. Ref.7

VAR_022829

Natural variant

124

1

C → R in JPS. Ref.6

VAR_015533

Natural variant

130

1

C → R in JPS. Ref.8

VAR_022830

Natural variant

338

1

A → D in CD. Ref.6

VAR_015534

Natural variant

376

1

C → Y in JPS. Ref.6

VAR_015535

Natural variant

443

1

R → C in JPS. Ref.7

VAR_022831

Natural variant

450

1

V → M Ref.12

VAR_041399

Natural variant

470

1

M → T in JPS. Ref.9

VAR_022832

Natural variant

486

1

R → Q in a gastric adenocarcinoma sample; somatic mutation. Ref.12

VAR_041400

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

532

Helix Strand Turn

Details...

Beta strand

59 – 62

4

Beta strand

64 – 66

3

Beta strand

75 – 88

14

Beta strand

94 – 101

8

Helix

106 – 111

6

Beta strand

120 – 125

6

Helix

130 – 133

4

Sequences

	Sequence		Length	Mass (Da)
	P36894-1 [UniParc]. Last modified March 15, 2005. Version 2. Checksum: 00CE2DDDA3A44170	FASTA	532	60,198
	10 20 30 40 50 60 MPQLYIYIRL LGAYLFIISR VQGQNLDSML HGTGMKSDSD QKKSENGVTL APEDTLPFLK 70 80 90 100 110 120 CYCSGHCPDD AINNTCITNG HCFAIIEEDD QGETTLASGC MKYEGSDFQC KDSPKAQLRR 130 140 150 160 170 180 TIECCRTNLC NQYLQPTLPP VVIGPFFDGS IRWLVLLISM AVCIIAMIIF SSCFCYKHYC 190 200 210 220 230 240 KSISSRRRYN RDLEQDEAFI PVGESLKDLI DQSQSSGSGS GLPLLVQRTI AKQIQMVRQV 250 260 270 280 290 300 GKGRYGEVWM GKWRGEKVAV KVFFTTEEAS WFRETEIYQT VLMRHENILG FIAADIKGTG 310 320 330 340 350 360 SWTQLYLITD YHENGSLYDF LKCATLDTRA LLKLAYSAAC GLCHLHTEIY GTQGKPAIAH 370 380 390 400 410 420 RDLKSKNILI KKNGSCCIAD LGLAVKFNSD TNEVDVPLNT RVGTKRYMAP EVLDESLNKN 430 440 450 460 470 480 HFQPYIMADI YSFGLIIWEM ARRCITGGIV EEYQLPYYNM VPSDPSYEDM REVVCVKRLR 490 500 510 520 530 PIVSNRWNSD ECLRAVLKLM SECWAHNPAS RLTALRIKKT LAKMVESQDV KI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity." ten Dijke P., Ichijo H., Franzen P., Schulz P., Saras J., Toyoshima H., Heldin C.-H., Miyazono K. Oncogene 8:2879-2887(1993) [PubMed: 8397373] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT THR-2. Tissue: Placenta.
[2]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Testis.
[3]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-215; SER-216; SER-218 AND SER-220, MASS SPECTROMETRY. Tissue: Epithelium.
[4]	"Crystal structure of the BMP-2-BRIA ectodomain complex." Kirsch T., Sebald W., Dreyer M.K. Nat. Struct. Biol. 7:492-496(2000) [PubMed: 10881198] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 55-143 IN COMPLEX WITH BMP-2.
[5]	"Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis." Howe J.R., Bair J.L., Sayed M.G., Anderson M.E., Mitros F.A., Petersen G.M., Velculescu V.E., Traverso G., Vogelstein B. Nat. Genet. 28:184-187(2001) [PubMed: 11381269] [Abstract] Cited for: DISEASE.
[6]	"Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes." Zhou X.-P., Woodford-Richens K., Lehtonen R., Kurose K., Aldred M., Hampel H., Launonen V., Virta S., Pilarski R., Salovaara R., Bodmer W.F., Conrad B.A., Dunlop M., Hodgson S.V., Iwama T., Jaervinen H., Kellokumpu I., Kim J.C. , Leggett B., Markie D., Mecklin J.-P., Neale K., Phillips R., Piris J., Rozen P., Houlston R.S., Aaltonen L.A., Tomlinson I.P.M., Eng C. Am. J. Hum. Genet. 69:704-711(2001) [PubMed: 11536076] [Abstract] Cited for: VARIANTS JPS ARG-124 AND TYR-376, VARIANT CD ASP-338.
[7]	"Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis." Sayed M.G., Ahmed A.F., Ringold J.R., Anderson M.E., Bair J.L., Mitros F.A., Lynch H.T., Tinley S.T., Petersen G.M., Giardiello F.M., Vogelstein B., Howe J.R. Ann. Surg. Oncol. 9:901-906(2002) [PubMed: 12417513] [Abstract] Cited for: VARIANTS JPS ASP-62; TYR-82 AND CYS-443.
[8]	"Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers." Friedl W., Uhlhaas S., Schulmann K., Stolte M., Loff S., Back W., Mangold E., Stern M., Knaebel H.P., Sutter C., Weber R.G., Pistorius S., Burger B., Propping P. Hum. Genet. 111:108-111(2002) [PubMed: 12136244] [Abstract] Cited for: VARIANT JPS ARG-130.
[9]	"Identification of a novel BMPR1A germline mutation in a Korean juvenile polyposis patient without SMAD4 mutation." Kim I.J., Park J.H., Kang H.C., Kim K.H., Kim J.H., Ku J.L., Kang S.B., Park S.Y., Lee J.S., Park J.G. Clin. Genet. 63:126-130(2003) [PubMed: 12630959] [Abstract] Cited for: VARIANT JPS THR-470.
[10]	"Contiguous gene deletion within chromosome arm 10q is associated with juvenile polyposis of infancy, reflecting cooperation between the BMPR1A and PTEN tumor-suppressor genes." Delnatte C., Sanlaville D., Mougenot J.-F., Vermeesch J.-R., Houdayer C., Blois M.-C., Genevieve D., Goulet O., Fryns J.-P., Jaubert F., Vekemans M., Lyonnet S., Romana S., Eng C., Stoppa-Lyonnet D. Am. J. Hum. Genet. 78:1066-1074(2006) [PubMed: 16685657] [Abstract] Cited for: INVOLVEMENT IN JUVENILE POLYPOSIS OF INFANCY.
[11]	"Mapping of hereditary mixed polyposis syndrome (HMPS) to chromosome 10q23 by genomewide high-density single nucleotide polymorphism (SNP) scan and identification of BMPR1A loss of function." Cao X., Eu K.W., Kumarasinghe M.P., Li H.H., Loi C., Cheah P.Y. J. Med. Genet. 43:E13-E13(2006) [PubMed: 16525031] [Abstract] Cited for: INVOLVEMENT IN HEREDITARY MIXED POLYPOSIS SYNDROME 2.
[12]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] THR-2; TYR-58; CYS-443; MET-450 AND GLN-486.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBLGenBankDDBJ

Z22535 mRNA. Translation: CAA80257.1.
BC028383 mRNA. Translation: AAH28383.1.

IPI

IPI00005731.

PIR

I37163.

RefSeq

NP_004320.2.

UniGene

Hs.524477

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1ES7	X-ray	2.90	B/D	55-143	[»]
1REW	X-ray	1.86	C/D	24-152	[»]
2GOO	X-ray	2.20	B/E	24-152	[»]
2H62	X-ray	1.85	C	24-152	[»]
2H64	X-ray	1.92	B	24-152	[»]
2K3G	NMR	-	A	52-152	[»]
2QJ9	X-ray	2.44	C/D	24-152	[»]
2QJA	X-ray	2.60	C/D	24-152	[»]
2QJB	X-ray	2.50	C/D	24-152	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:5793N.

Proteomic databases

PRIDE

P36894.

Genome annotation databases

Ensembl

ENSG00000107779. Homo sapiens. [Contig view]

GeneID

657.

KEGG

hsa:657.

Organism-specific databases

GeneCards

GC10P088506.

H-InvDB

HIX0026073.
HIX0036564.

HGNC

HGNC:1076. BMPR1A.

HPA

CAB019398.

MIM

158350. phenotype.
174900. phenotype.
601299. gene.
610069. phenotype.
612242. phenotype.

Orphanet

2929. Juvenile gastrointestinal polyposis.
79076. Juvenile polyposis of infancy.
157794. Mixed polyposis syndrome, hereditary.

PharmGKB

PA25386.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P36894.

HOVERGEN

P36894.

OMA

P36894. DECLRAM.

Enzyme and pathway databases

BRENDA

2.7.10.2. 247.
2.7.11.30. 247.

Pathway_Interaction_DB

bmppathway. BMP receptor signaling.

Reactome

REACT_12034. Signaling by BMP.

Gene expression databases

ArrayExpress

P36894.

Bgee

P36894.

CleanEx

HS_BMPR1A.

Family and domain databases

InterPro

IPR000472. Activin_rcpt.
IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_pkinase-rel.
IPR008271. Ser_thr_pkin_AS.
IPR003605. TGF_beta_rcpt_GS.
[Graphical view]

Pfam

PF01064. Activin_recp. 1 hit.
PF00069. Pkinase. 1 hit.
PF08515. TGF_beta_GS. 1 hit.
[Graphical view]

ProDom

PD000001. Prot_kinase. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00467. GS. 1 hit.
[Graphical view]

PROSITE

PS51256. GS. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

2672.

SOURCE

Search...

Entry information

Entry name

BMR1A_HUMAN

Accession

Primary (citable) accession number: P36894
Secondary accession number(s): Q8NEN8

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	March 15, 2005
Last modified:	June 16, 2009
This is version 115 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)