BMPR2

BMPR2
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	2HLQ, 3G2F
Identifikatori
Aliasi	BMPR2
Vanjski ID-jevi	OMIM: 600799 MGI: 1095407 HomoloGene: 929 GeneCards: BMPR2
Lokacija gena (čovjek)
Hrom.	Hromosom 2 (čovjek)
Kraj	202,567,751 bp
Lokacija gena (miš)
Hrom.	Hromosom 1 (miš)
Kraj	59,918,173 bp
Ontologija gena
Molekularna funkcija	• transmembrane receptor protein serine/threonine kinase activity; • ATP binding; • protein serine/threonine kinase activity; • activin receptor activity, type II; • BMP binding; • protein kinase activity; • GO:0001948, GO:0016582 vezivanje za proteine; • kinase activity; • growth factor binding; • vezivanje iona metala; • nucleotide binding; • aktivnost sa transferazom; • BMP receptor activity; • transforming growth factor beta-activated receptor activity; • transforming growth factor beta receptor activity, type II; • SMAD binding;
Ćelijska komponenta	• integral component of membrane; • Kaveole; • spanning component of plasma membrane; • dendrit; • soma; • membrana; • cell surface; • integral component of plasma membrane; • ćelijska membrana; • citoplazma; • basal plasma membrane; • apical plasma membrane; • Vanćelijsko; • nukleoplazma; • GO:0097483, GO:0097481 postsynaptic density; • receptor complex;
Biološki proces	• endothelial cell apoptotic process; • positive regulation of epithelial cell migration; • transmembrane receptor protein serine/threonine kinase signaling pathway; • negative regulation of vasoconstriction; • positive regulation of endothelial cell proliferation; • endochondral bone morphogenesis; • positive regulation of endothelial cell migration; • lymphangiogenesis; • positive regulation of pathway-restricted SMAD protein phosphorylation; • anterior/posterior pattern specification; • regulation of cell population proliferation; • lung alveolus development; • negative regulation of cell growth; • transcription by RNA polymerase II; • regulation of lung blood pressure; • protein phosphorylation; • positive regulation of axon extension involved in axon guidance; • artery development; • blood vessel remodeling; • BMP signaling pathway; • mesoderm formation; • vascular endothelial growth factor receptor signaling pathway; • GO:0072468 Transdukcija signala; • proteoglycan biosynthetic process; • positive regulation of cartilage development; • maternal placenta development; • endothelial cell proliferation; • cellular response to starvation; • negative regulation of DNA biosynthetic process; • chondrocyte development; • negative regulation of systemic arterial blood pressure; • positive regulation of osteoblast differentiation; • retina vasculature development in camera-type eye; • cellular response to BMP stimulus; • Fosforilacija; • venous blood vessel development; • brain development; • retina development in camera-type eye; • positive regulation of BMP signaling pathway; • limb development; • positive regulation of bone mineralization; • negative regulation of chondrocyte proliferation; • lymphatic endothelial cell differentiation; • mitral valve morphogenesis; • pharyngeal arch artery morphogenesis; • tricuspid valve morphogenesis; • outflow tract septum morphogenesis; • atrioventricular valve morphogenesis; • activin receptor signaling pathway; • cardiac muscle tissue development; • outflow tract morphogenesis; • endocardial cushion development; • negative regulation of cell proliferation involved in heart valve morphogenesis; • positive regulation of ossification; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • ventricular septum morphogenesis; • atrial septum morphogenesis; • semi-lunar valve development; • transforming growth factor beta receptor signaling pathway; • pattern specification process; • aortic valve development; • pulmonary valve development;
	Izvori:Amigo / QuickGO
Ortolozi
	659
	12168
	ENSG00000204217
	ENSMUSG00000067336
	Q13873
	O35607
	NM_001204; NM_033346
	NM_007561
	NP_001195
	NP_031587
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Receptor koštanog morfogenetskog proteina tip II ili jest enzim koji je kod ljudi kodiran genom BMPR2 sa hromosoma 2. To je serin/treonin receptor kinaza za vezanje koštane morfogenetske prpteine, članove TGF beta liganada, konatporodice liganada ji uključenih u parakrinu signalizaciju. BMP učestvuju u nizu ćelijskih funkcija, uključujući osteogenezu, ćelijski rast i diferencijaciju. Signalizacija u BMP-putu počinje vezivanjem BMP-a za receptor tipa II. Ovo uzrokuje regrutaciju BMP tipa I receptora, koji fosforilizira. Receptor tipa I fosforilira regulator transkripcije R-SMAD.

Amiokiselininska sekvenca

Dužina polipeptidnog lanca je 1 038 aminokiselina, a molekulska težina 115.201 Da.^[5]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MTSSLQRPWR	VPWLPWTILL	VSTAAASQNQ	ERLCAFKDPY	QQDLGIGESR
ISHENGTILC	SKGSTCYGLW	EKSKGDINLV	KQGCWSHIGD	PQECHYEECV
VTTTPPSIQN	GTYRFCCCST	DLCNVNFTEN	FPPPDTTPLS	PPHSFNRDET
IIIALASVSV	LAVLIVALCF	GYRMLTGDRK	QGLHSMNMME	AAASEPSLDL
DNLKLLELIG	RGRYGAVYKG	SLDERPVAVK	VFSFANRQNF	INEKNIYRVP
LMEHDNIARF	IVGDERVTAD	GRMEYLLVME	YYPNGSLCKY	LSLHTSDWVS
SCRLAHSVTR	GLAYLHTELP	RGDHYKPAIS	HRDLNSRNVL	VKNDGTCVIS
DFGLSMRLTG	NRLVRPGEED	NAAISEVGTI	RYMAPEVLEG	AVNLRDCESA
LKQVDMYALG	LIYWEIFMRC	TDLFPGESVP	EYQMAFQTEV	GNHPTFEDMQ
VLVSREKQRP	KFPEAWKENS	LAVRSLKETI	EDCWDQDAEA	RLTAQCAEER
MAELMMIWER	NKSVSPTVNP	MSTAMQNERN	LSHNRRVPKI	GPYPDYSSSS
YIEDSIHHTD	SIVKNISSEH	SMSSTPLTIG	EKNRNSINYE	RQQAQARIPS
PETSVTSLST	NTTTTNTTGL	TPSTGMTTIS	EMPYPDETNL	HTTNVAQSIG
PTPVCLQLTE	EDLETNKLDP	KEVDKNLKES	SDENLMEHSL	KQFSGPDPLS
STSSSLLYPL	IKLAVEATGQ	QDFTQTANGQ	ACLIPDVLPT	QIYPLPKQQN
LPKRPTSLPL	NTKNSTKEPR	LKFGSKHKSN	LKQVETGVAK	MNTINAAEPH
VVTVTMNGVA	GRNHSVNSHA	ATTQYANGTV	LSGQTTNIVT	HRAQEMLQNQ
FIGEDTRLNI	NSSPDEHEPL	LRREQQAGHD	EGVLDRLVDR	RERPLEGGRT
NSNNNNSNPC	SEQDVLAQGV	PSTAADPGPS	KPRRAQRPNS	LDLSATNVLD
GSSIQIGEST	QDGKSGSGEK	IKKRVKTPYS	LKRWRPSTWV	ISTESLDCEV
NNNGSNRAVH	SKSSTAVYLA	EGGTATTMVS	KDIGMNCL

Funkcija

Za razliku od TGFβ receptora tipa II, koji ima visok afinitet za TGF-β1, BMPR2 nema visok afinitet za BMP-2, BMP-7 i BMP-4, osim ako nije ko-eksprimiran sa BMP receptorom tipa I. Vezanjem liganda, formira receptorski kompleks koji se sastoji od dvije transmembrane tipa II i dvije serin/treonin-kinaze tipa I. Receptori tipa II fosforiliraju i aktiviraju receptore tipa I koji zatim autofosforilirajući vežu i aktiviraju SMAD transkripcijske regulatore. Veže se za BMP-7, BMP-2 i, manje efikasno, za BMP-4. Vezivanje je slabo, ali pojačano prisustvom receptora tipa I za BMP.^[6] U TGF-beta signalizaciji svi receptori postoje u homodimerima prije vezivanja liganda. U slučaju receptora BMP, samo mali dio receptora postoji u homomernim oblicima prije vezivanja ligand. Jednom kada se ligand veže za receptor, povećava se količina oligomera homomernih receptora, što sugerira da se ravnoteža pomjera prema homodimernom obliku. Nizak afinitet za ligande sugerira da BMPR2 se može razlikovati od drugih TGF beta receptora tipa II po tome što ligand može prvo vezati receptor tipa I.^[7]

Razvoj oocita

BMPR2 se eksprimira i na ljudskim i na životinjskim granuloznim ćelijama i ključni je receptor za koštani morfogenetski protein 15 (BMP15) i faktor diferencijacije rasta 9 (GDF 9). Ove dvije proteinske signalne molekule i njihovi BMPR2 posredovani efekti imaju važnu ulogu u razvoju folikula u pripremi za ovulaciju.^[8] Međutim, BMPR2 ne može da veže BMP15 i GDF9 bez pomoći receptora koštanog morfogenetskog proteina 1B (BMPR1B) i receptora 1 transformacijskog faktora rasta β (TGFβR1). Postoje dokazi da je BMPR2 signalni put poremećen u slučaju sindroma policistastih jajnika, vjerovatno hiperaldosterizmom.^[9]

Čini se da hormoni estrogen i folikul-stimulirajući hormon (FSH) imaju ulogu u regulaciji ekspresije BMPR2 u granuloza ćelijamama. Eksperimentalni tretman na životinjskim modelima sa estradiolom sa ili bez FSH povećao je ekspresiju iRNK BMPR2, dok je tretman samim FSH smanjio ekspresiju BMPR2. Međutim, kod ljudskih ćelija tumora sličnih granulozi (KGN), tretman sa FSH povećao je ekspresiju BMPR2.^[10]

Klinički značaj

Inaktivirajuća mutacija u "BMPR2" genu je povezana sa plućnom arterijskom hipertenzijom.^[11]

BMPR2 djeluje tako da inhibira proliferaciju vaskularnog glatkog mišićnog tkiva. Djeluje tako što podstiče preživljavanje endotelnih ćelija plućnih arterija, čime sprečava oštećenje arterija i štetne upalne reakcije. Također inhibira proliferaciju plućnih arterija, kao odgovor na faktore rasta, što sprečava zatvaranje arterija proliferacijom endotelnih ćelija.^[12] Kada se ovaj gen inhibira, glatki mišići krvnih sudova proliferiraju i mogu uzrokovati plućnu hipertenziju, što, između ostalog, može dovesti do poremećaja cor pulmonale, stanja koje uzrokuje otkazivanje desne strane srca. Disfunkcija BMPR2 također može dovesti do povišenja plućnog arterijskog pritiska zbog štetnog odgovora plućnog kola na ozljedu.^[12]

Posebno je važno pregledati mutacije BMPR2 kod srodnika pacijenata sa idiopatskom plućnom hipertenzijom, jer su ove mutacije prisutne u >70% porodičnih slučajeva.^[12]

Postojale su studije koje su povezivale BMPR2 s povećanjem pritiska PA ,uzrokovanog vježbanjem mjerenjem brzine trokvržične regurgitacije ehokardiografijom.^[13]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000204217 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000067336 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "UniProt, Q13873" (jezik: engleski). Pristupljeno 16. 11. 2021.
^ Gilboa L, Nohe A, Geissendörfer T, Sebald W, Henis YI, Knaus P (mart 2000). "Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors". Mol. Biol. Cell. 11 (3): 1023–35. doi:10.1091/mbc.11.3.1023. PMC 14828. PMID 10712517.
^ Kirsch T, Nickel J, Sebald W (juli 2000). "BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II". EMBO J. 19 (13): 3314–24. doi:10.1093/emboj/19.13.3314. PMC 313944. PMID 10880444.
^ Edwards SJ, Reader KL, Lun S, Western A, Lawrence S, McNatty KP, Juengel JL (2008). "The cooperative effect of growth and differentiation factor-9 and bone morphogenetic protein (BMP)-15 on granulosa cell function is modulated primarily through BMP receptor II". Endocrinology. 149 (3): 1026–30. doi:10.1210/en.2007-1328. PMID 18063682.
^ de Resende LO, Vireque AA, Santana LF, Moreno DA, de Sá Rosa e Silva AC, Ferriani RA, Scrideli CA, Reis RM (2012). "Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation". J. Assist. Reprod. Genet. 29 (10): 1057–65. doi:10.1007/s10815-012-9825-8. PMC 3492567. PMID 22825968.
^ Paradis F, Novak S, Murdoch GK, Dyck MK, Dixon WT, Foxcroft GR (2009). "Temporal regulation of BMP2, BMP6, BMP15, GDF9, BMPR1A, BMPR1B, BMPR2 and TGFBR1 mRNA expression in the oocyte, granulosa and theca cells of developing preovulatory follicles in the pig". Reproduction. 138 (1): 115–29. doi:10.1530/REP-08-0538. PMID 19359354.
^ Rabinovitch M (decembar 2012). "Molecular pathogenesis of pulmonary arterial hypertension". J. Clin. Invest. 122 (12): 4306–13. doi:10.1172/JCI60658. PMC 3533531. PMID 23202738.
^ ^a ^b ^c Rabinovitch, Marlene. "Rescuing the BMPR2 Pathway: How and Where Can We Intervene?". Pulmonary Hypertension Association. Pristupljeno 29. 1. 2015.^{[mrtav link]}
^ Grünig E, Weissmann S, Ehlken N, Fijalkowska A, Fischer C, Fourme T, Galié N, Ghofrani A, Harrison RE, Huez S, Humbert M, Janssen B, Kober J, Koehler R, Machado RD, Mereles D, Naeije R, Olschewski H, Provencher S, Reichenberger F, Retailleau K, Rocchi G, Simonneau G, Torbicki A, Trembath R, Seeger W (2009). "Stress Doppler echocardiography in relatives of patients with idiopathic and familial pulmonary arterial hypertension: results of a multicenter European analysis of pulmonary artery pressure response to exercise and hypoxia". Circulation. 119 (13): 1747–57. doi:10.1161/CIRCULATIONAHA.108.800938. PMID 19307479.

Vanjski linkovi

BMPR2 gene variant database
GeneReviews/NCBI/NIH/UW entry on Heritable Pulmonary Arterial Hypertension
OMIM entries on Heritable Pulmonary Arterial Hypertension
Lokacija ljudskog genoma BMPR2 i stranica sa detaljima o genu BMPR2 u UCSC Genome Browseru.

Šablon:Signalizacija TGF-beta

Portal Biologija

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000204217 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000067336 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[UniProt-5] "UniProt, Q13873" (jezik: engleski). Pristupljeno 16. 11. 2021.

[complexes-6] Gilboa L, Nohe A, Geissendörfer T, Sebald W, Henis YI, Knaus P (mart 2000). "Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors". Mol. Biol. Cell. 11 (3): 1023–35. doi:10.1091/mbc.11.3.1023. PMC 14828. PMID 10712517.

[pmid10880444-7] Kirsch T, Nickel J, Sebald W (juli 2000). "BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II". EMBO J. 19 (13): 3314–24. doi:10.1093/emboj/19.13.3314. PMC 313944. PMID 10880444.

[pmid18063682-8] Edwards SJ, Reader KL, Lun S, Western A, Lawrence S, McNatty KP, Juengel JL (2008). "The cooperative effect of growth and differentiation factor-9 and bone morphogenetic protein (BMP)-15 on granulosa cell function is modulated primarily through BMP receptor II". Endocrinology. 149 (3): 1026–30. doi:10.1210/en.2007-1328. PMID 18063682.

[pmid22825968-9] Resende LO, Vireque AA, Santana LF, Moreno DA, de Sá Rosa e Silva AC, Ferriani RA, Scrideli CA, Reis RM (2012). "Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation". J. Assist. Reprod. Genet. 29 (10): 1057–65. doi:10.1007/s10815-012-9825-8. PMC 3492567. PMID 22825968.

[pmid19359354-10] Paradis F, Novak S, Murdoch GK, Dyck MK, Dixon WT, Foxcroft GR (2009). "Temporal regulation of BMP2, BMP6, BMP15, GDF9, BMPR1A, BMPR1B, BMPR2 and TGFBR1 mRNA expression in the oocyte, granulosa and theca cells of developing preovulatory follicles in the pig". Reproduction. 138 (1): 115–29. doi:10.1530/REP-08-0538. PMID 19359354.

[pmid23202738-11] Rabinovitch M (decembar 2012). "Molecular pathogenesis of pulmonary arterial hypertension". J. Clin. Invest. 122 (12): 4306–13. doi:10.1172/JCI60658. PMC 3533531. PMID 23202738.

[phareference-12] Rabinovitch, Marlene. "Rescuing the BMPR2 Pathway: How and Where Can We Intervene?". Pulmonary Hypertension Association. Pristupljeno 29. 1. 2015.^{[mrtav link]}

[pmid19307479-13] Grünig E, Weissmann S, Ehlken N, Fijalkowska A, Fischer C, Fourme T, Galié N, Ghofrani A, Harrison RE, Huez S, Humbert M, Janssen B, Kober J, Koehler R, Machado RD, Mereles D, Naeije R, Olschewski H, Provencher S, Reichenberger F, Retailleau K, Rocchi G, Simonneau G, Torbicki A, Trembath R, Seeger W (2009). "Stress Doppler echocardiography in relatives of patients with idiopathic and familial pulmonary arterial hypertension: results of a multicenter European analysis of pulmonary artery pressure response to exercise and hypoxia". Circulation. 119 (13): 1747–57. doi:10.1161/CIRCULATIONAHA.108.800938. PMID 19307479.

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p r u Enzimi
Teme	Aktivno mjesto Alosterna regulacija Difuzijski limitirani enzim EC broj Enzimska kataliza Inhibicija enzimskih reakcija Kinetika enzima Koenzim Kooperativnost Lineweaver–Burkov dijagram Michaelis–Mentenova kinetika Mjesto vezanja Spisak enzima
Tipovi	EC1 Oksidoreduktaze/spisak EC2 Transferaze/spisak EC3 Hidrolaze/spisak EC4 Lijaze/spisak EC5 Izomeraze/spisak EC6 Ligaze/spisak