Reviewed, UniProtKB/Swiss-Prot Q13873 (BMPR2_HUMAN)

Names and origin

Protein names

Recommended name:
    Bone morphogenetic protein receptor type-2
    EC=2.7.11.30
Alternative name(s):
    Bone morphogenetic protein receptor type II
    BMP type II receptor
    BMPR-II

Gene names

Name:	BMPR2
Synonyms:	PPH1

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	1038 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. Binds to BMP-7, BMP-2 and, less efficiently, BMP-4. Binding is weak but enhanced by the presence of type I receptors for BMPs.
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 heart and liver.
Involvement in disease	Defects in BMPR2 are the cause of primary pulmonary hypertension (PPH1) [MIM:178600]. PPH1 is a rare autosomal dominant disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial PPH1 is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs. Defects in BMPR2 are a cause of pulmonary venoocclusive disease (PVOD) [MIM:265450]. PVOD is a rare form of pulmonary hypertension in which the vascular changes originate in the small pulmonary veins and venules. The pathogenesis is unknown and any link with PPH1 has been speculative. The finding of PVOD associated with a BMPR2 mutation reveals a possible pathogenetic connection with PPH1.
Sequence similarities	Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily. 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	Glycoprotein
Gene Ontology (GO)
Biological process	BMP signaling pathway Inferred from direct assay. Source: UniProtKB alveolus development Inferred from sequence or structural similarity. Source: UniProtKB anterior/posterior pattern formation Inferred from sequence or structural similarity. Source: UniProtKB mesoderm formation Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of systemic arterial blood pressure Inferred from mutant phenotype. Source: UniProtKB negative regulation of vasoconstriction Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of bone mineralization Inferred from mutant phenotype. Source: UniProtKB positive regulation of osteoblast differentiation Inferred from mutant phenotype. Source: UniProtKB protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro regulation of cell proliferation Inferred from mutant phenotype. Source: HGNC regulation of lung blood pressure Inferred from mutant phenotype. Source: UniProtKB transcription from RNA polymerase II promoter Inferred from mutant phenotype. Source: UniProtKB vascular endothelial growth factor receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	cell surface Inferred from sequence or structural similarity. Source: UniProtKB integral to plasma membrane Inferred from direct assay. Source: UniProtKB
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW manganese ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from physical interaction. Source: IntAct transforming growth factor beta receptor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
C4bp	Q91X48	1	EBI-527196,EBI-527325	From a different organism.
Prkcb1	P68404	2	EBI-527196,EBI-397048	From a different organism.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 26	26	Potential
	Chain	27 – 1038	1012	Bone morphogenetic protein receptor type-2		PRO_0000024415
Regions
	Topological domain	27 – 150	124	Extracellular Potential
	Transmembrane	151 – 171	21	Potential
	Topological domain	172 – 1038	867	Cytoplasmic Potential
	Domain	203 – 504	302	Protein kinase
	Nucleotide binding	209 – 217	9	ATP By similarity
	Compositional bias	547 – 550	4	Poly-Ser
	Compositional bias	610 – 618	9	Poly-Thr
	Compositional bias	901 – 908	8	Poly-Asn
Sites
	Active site	333	1	Proton acceptor By similarity
	Binding site	230	1	ATP By similarity
Amino acid modifications
	Glycosylation	55	1	N-linked (GlcNAc...) Potential
	Glycosylation	110	1	N-linked (GlcNAc...) Potential
	Glycosylation	126	1	N-linked (GlcNAc...) Potential
	Disulfide bond	34 ↔ 66		By similarity
	Disulfide bond	94 ↔ 117		By similarity
Natural variations
	Natural variant	60	1	C → Y in PPH1.		VAR_013670
	Natural variant	82	1	Q → H in PPH1.		VAR_033109
	Natural variant	117	1	C → Y in PPH1.		VAR_013671
	Natural variant	118	1	C → W in PPH1.		VAR_013672
	Natural variant	123	1	C → R in PPH1.		VAR_013673
	Natural variant	123	1	C → S in PPH1.		VAR_013674
	Natural variant	182	1	G → D in PPH1.		VAR_033110
	Natural variant	224	1	E → D		VAR_013675
	Natural variant	347	1	C → Y in PPH1.		VAR_013676
	Natural variant	420	1	C → R in PPH1.		VAR_013677
	Natural variant	483	1	C → R in PPH1; sporadic.		VAR_013678
	Natural variant	485	1	D → G in PPH1; complete loss of function.		VAR_013679
	Natural variant	491	1	R → Q in PPH1; sporadic.		VAR_013680
	Natural variant	491	1	R → W in PPH1.		VAR_013681
	Natural variant	512	1	K → T in PPH1.		VAR_013682
	Natural variant	519	1	N → K in PPH1.		VAR_013683
	Natural variant	775	1	S → N: dbSNP rs2228545.		VAR_019996
	Natural variant	899	1	R → P in PPH1; leads to constitutive activation of the MAPK14 pathway.		VAR_033111
Experimental info
	Sequence conflict	828	1	G → R in CAA88759. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q13873-1 [UniParc]. Last modified December 1, 2000. Version 2. Checksum: 1389923CE574B913	FASTA	1,038	115,201
	10 20 30 40 50 60 MTSSLQRPWR VPWLPWTILL VSTAAASQNQ ERLCAFKDPY QQDLGIGESR ISHENGTILC 70 80 90 100 110 120 SKGSTCYGLW EKSKGDINLV KQGCWSHIGD PQECHYEECV VTTTPPSIQN GTYRFCCCST 130 140 150 160 170 180 DLCNVNFTEN FPPPDTTPLS PPHSFNRDET IIIALASVSV LAVLIVALCF GYRMLTGDRK 190 200 210 220 230 240 QGLHSMNMME AAASEPSLDL DNLKLLELIG RGRYGAVYKG SLDERPVAVK VFSFANRQNF 250 260 270 280 290 300 INEKNIYRVP LMEHDNIARF IVGDERVTAD GRMEYLLVME YYPNGSLCKY LSLHTSDWVS 310 320 330 340 350 360 SCRLAHSVTR GLAYLHTELP RGDHYKPAIS HRDLNSRNVL VKNDGTCVIS DFGLSMRLTG 370 380 390 400 410 420 NRLVRPGEED NAAISEVGTI RYMAPEVLEG AVNLRDCESA LKQVDMYALG LIYWEIFMRC 430 440 450 460 470 480 TDLFPGESVP EYQMAFQTEV GNHPTFEDMQ VLVSREKQRP KFPEAWKENS LAVRSLKETI 490 500 510 520 530 540 EDCWDQDAEA RLTAQCAEER MAELMMIWER NKSVSPTVNP MSTAMQNERN LSHNRRVPKI 550 560 570 580 590 600 GPYPDYSSSS YIEDSIHHTD SIVKNISSEH SMSSTPLTIG EKNRNSINYE RQQAQARIPS 610 620 630 640 650 660 PETSVTSLST NTTTTNTTGL TPSTGMTTIS EMPYPDETNL HTTNVAQSIG PTPVCLQLTE 670 680 690 700 710 720 EDLETNKLDP KEVDKNLKES SDENLMEHSL KQFSGPDPLS STSSSLLYPL IKLAVEATGQ 730 740 750 760 770 780 QDFTQTANGQ ACLIPDVLPT QIYPLPKQQN LPKRPTSLPL NTKNSTKEPR LKFGSKHKSN 790 800 810 820 830 840 LKQVETGVAK MNTINAAEPH VVTVTMNGVA GRNHSVNSHA ATTQYANGTV LSGQTTNIVT 850 860 870 880 890 900 HRAQEMLQNQ FIGEDTRLNI NSSPDEHEPL LRREQQAGHD EGVLDRLVDR RERPLEGGRT 910 920 930 940 950 960 NSNNNNSNPC SEQDVLAQGV PSTAADPGPS KPRRAQRPNS LDLSATNVLD GSSIQIGEST 970 980 990 1000 1010 1020 QDGKSGSGEK IKKRVKTPYS LKRWRPSTWV ISTESLDCEV NNNGSNRAVH SKSSTAVYLA 1030 EGGTATTMVS KDIGMNCL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of a human type II receptor for bone morphogenetic proteins." Rosenzweig B.L., Imamura T., Okadome T., Cox G.N., Yamashita H., ten Dijke P., Heldin C., Miyazono K. Proc. Natl. Acad. Sci. U.S.A. 92:7632-7636(1995) [PubMed: 7644468] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Substantia nigra.
[2]	"Identification of a human type II receptor for bone morphogenetic protein-4 that forms differential heteromeric complexes with bone morphogenetic protein type I receptors." Nohno T., Ishikawa T., Saito T., Hosokawa K., Noji S., Wosing D.H., Rosenbaum J.S. J. Biol. Chem. 270:22522-22526(1995) [PubMed: 7673243] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Skin fibroblast.
[3]	"Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-beta receptor." Kawabata M., Chytil A., Moses H.L. J. Biol. Chem. 270:5625-5630(1995) [PubMed: 7890683] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"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: Skin.
[5]	"Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene." Deng Z., Morse J.H., Slager S.L., Cuervo N., Moore K.J., Venetos G., Kalachikov S., Cayanis E., Fischer S.G., Barst R.J., Hodge S.E., Knowles J.A. Am. J. Hum. Genet. 67:737-744(2000) [PubMed: 10903931] [Abstract] Cited for: VARIANTS PPH1 GLN-491 AND TRP-491.
[6]	"Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family." Thomson J.R., Machado R.D., Pauciulo M.W., Morgan N.V., Humbert M., Elliott G.C., Ward K., Yacoub M., Mikhail G., Rogers P., Newman J.H., Wheeler L., Higenbottam T., Gibbs J.S.R., Egan J., Crozier A., Peacock A., Allcock R. , Corris P., Loyd J.E., Trembath R.C., Nichols W.C. J. Med. Genet. 37:741-745(2000) [PubMed: 11015450] [Abstract] Cited for: VARIANTS PPH1 TYR-60; TYR-117 AND ARG-483.
[7]	"Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension." Lane K.B., Machado R.D., Pauciulo M.W., Thomson J.R., Phillips J.A. III, Loyd J.E., Nichols W.C., Trembath R.C., Aldred M., Brannon C.A., Conneally P.M., Foroud T., Fretwell N., Gaddipati R., Koller D., Loyd E.J., Morgan N.V., Newman J.H. , Prince M.A., Vilarino Gueell C., Wheeler L. Nat. Genet. 26:81-84(2000) [PubMed: 10973254] [Abstract] Cited for: VARIANTS PPH1 TRP-118; TYR-347 AND GLY-485.
[8]	"BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension." Machado R.D., Pauciulo M.W., Thomson J.R., Lane K.B., Morgan N.V., Wheeler L., Phillips J.A. III, Newman J.H., Williams D., Galie N., Manes A., McNeil K., Yacoub M., Mikhail G., Rogers P., Corris P., Humbert M., Donnai D. , Martensson G., Tranebjaerg L., Loyd J.E., Trembath R.C., Nichols W.C. Am. J. Hum. Genet. 68:92-102(2001) [PubMed: 11115378] [Abstract] Cited for: VARIANTS PPH1 ARG-123; SER-123; ARG-420 AND THR-512, VARIANT ASP-224, CHARACTERIZATION OF VARIANT PPH1 GLY-485.
[9]	"BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives." Humbert M., Deng Z., Simonneau G., Barst R.J., Sitbon O., Wolf M., Cuervo N., Moore K.J., Hodge S.E., Knowles J.A., Morse J.H. Eur. Respir. J. 20:518-523(2002) [PubMed: 12358323] [Abstract] Cited for: VARIANTS PPH1 HIS-82; ASP-182 AND ARG-483.
[10]	"Pulmonary veno-occlusive disease caused by an inherited mutation in bone morphogenetic protein receptor II." Runo J.R., Vnencak-Jones C.L., Prince M., Loyd J.E., Wheeler L., Robbins I.M., Lane K.B., Newman J.H., Johnson J., Nichols W.C., Phillips J.A. III Am. J. Respir. Crit. Care Med. 167:889-894(2003) [PubMed: 12446270] [Abstract] Cited for: INVOLVEMENT IN PVOD.
[11]	"BMPR2 mutations have short lifetime expectancy in primary pulmonary hypertension." Sankelo M., Flanagan J.A., Machado R., Harrison R., Rudarakanchana N., Morrell N., Dixon M., Halme M., Puolijoki H., Kere J., Elomaa O., Kupari M., Raeisaenen-Sokolowski A., Trembath R.C., Laitinen T. Hum. Mutat. 26:119-124(2005) [PubMed: 15965979] [Abstract] Cited for: VARIANT PPH1 PRO-899, CHARACTERIZATION OF VARIANT PPH1 PRO-899.
[12]	"Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension." Machado R.D., Aldred M.A., James V., Harrison R.E., Patel B., Schwalbe E.C., Gruenig E., Janssen B., Koehler R., Seeger W., Eickelberg O., Olschewski H., Elliott C.G., Glissmeyer E., Carlquist J., Kim M., Torbicki A., Fijalkowska A. , Szewczyk G., Parma J., Abramowicz M.J., Galie N., Morisaki H., Kyotani S., Nakanishi N., Morisaki T., Humbert M., Simonneau G., Sitbon O., Soubrier F., Coulet F., Morrell N.W., Trembath R.C. Hum. Mutat. 27:121-132(2006) [PubMed: 16429395] [Abstract] Cited for: INVOLVEMENT IN PVOD.
[13]	"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: VARIANT [LARGE SCALE ANALYSIS] ASN-775.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	Z48923 mRNA. Translation: CAA88759.1. D50516 mRNA. Translation: BAA09094.1. U20165 mRNA. Translation: AAC50105.1. BC052985 mRNA. Translation: AAH52985.1.
PIR	I38935.
RefSeq	NP_001195.2.
UniGene	Hs.471119
3D structure databases
HSSP	HSSP built from PDB template 1IAS based on UniProtKB P36897.
SMR	Q13873. Positions 33-131.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP:5794N. DIP:5941N. DIP:5942N.
IntAct	Q13873.
PTM databases
PhosphoSite	Q13873.
Genome annotation databases
Ensembl	ENSG00000204217. Homo sapiens. [Contig view]
GeneID	659.
KEGG	hsa:659.
Organism-specific databases
H-InvDB	HIX0002749.
HGNC	HGNC:1078. BMPR2.
HPA	HPA017385.
MIM	178600. phenotype. 265450. phenotype. 600799. gene.
Orphanet	422. Pulmonary arterial hypertension. 31837. Pulmonary venoocclusive disease.
PharmGKB	PA25388.
GenAtlas