| Structural highlights
Disease
[ACVL1_HUMAN] Defects in ACVRL1 are the cause of hereditary hemorrhagic telangiectasia type 2 (HHT2) [MIM:600376]; also known as Osler-Rendu-Weber syndrome 2 (ORW2). HHT2 is an autosomal dominant multisystemic vascular dysplasia, characterized by recurrent epistaxis, muco-cutaneous telangiectases, gastro-intestinal hemorrhage, and pulmonary, cerebral and hepatic arteriovenous malformations; all secondary manifestations of the underlying vascular dysplasia.[1] [2] [3] [4] [5] [6] [7] [8] [9]
Function
[ACVL1_HUMAN] Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development. 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. May bind activin as well.[10] [11] [BMP10_HUMAN] Required for maintaining the proliferative activity of embryonic cardiomyocytes by preventing premature activation of the negative cell cycle regulator CDKN1C/p57KIP and maintaining the required expression levels of cardiogenic factors such as MEF2C and NKX2-5. Acts as a ligand for ACVRL1/ALK1, BMPR1A/ALK3 and BMPR1B/ALK6, leading to activation of SMAD1, SMAD5 and SMAD8 transcription factors. Inhibits endothelial cell migration and growth. May reduce cell migration and cell matrix adhesion in breast cancer cell lines.[12] [13] [14]
Publication Abstract from PubMed
Activin receptor-like kinase 1 (ALK1)-mediated endothelial cell signalling in response to bone morphogenetic protein 9 (BMP9) and BMP10 is of significant importance in cardiovascular disease and cancer. However, detailed molecular mechanisms of ALK1-mediated signalling remain unclear. Here, we report crystal structures of the BMP10:ALK1 complex at 2.3 A and the prodomain-bound BMP9:ALK1 complex at 3.3 A. Structural analyses reveal a tripartite recognition mechanism that defines BMP9 and BMP10 specificity for ALK1, and predict that crossveinless 2 is not an inhibitor of BMP9, which is confirmed by experimental evidence. Introduction of BMP10-specific residues into BMP9 yields BMP10-like ligands with diminished signalling activity in C2C12 cells, validating the tripartite mechanism. The loss of osteogenic signalling in C2C12 does not translate into non-osteogenic activity in vivo and BMP10 also induces bone-formation. Collectively, these data provide insight into ALK1-mediated BMP9 and BMP10 signalling, facilitating therapeutic targeting of this important pathway.
Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms.,Salmon RM, Guo J, Wood JH, Tong Z, Beech JS, Lawera A, Yu M, Grainger DJ, Reckless J, Morrell NW, Li W Nat Commun. 2020 Apr 1;11(1):1621. doi: 10.1038/s41467-020-15425-3. PMID:32238803[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Berg JN, Gallione CJ, Stenzel TT, Johnson DW, Allen WP, Schwartz CE, Jackson CE, Porteous ME, Marchuk DA. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet. 1997 Jul;61(1):60-7. PMID:9245985 doi:S0002-9297(07)64277-3
- ↑ Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, Stenzel TT, Speer M, Pericak-Vance MA, Diamond A, Guttmacher AE, Jackson CE, Attisano L, Kucherlapati R, Porteous ME, Marchuk DA. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996 Jun;13(2):189-95. PMID:8640225 doi:10.1038/ng0696-189
- ↑ Klaus DJ, Gallione CJ, Anthony K, Yeh EY, Yu J, Lux A, Johnson DW, Marchuk DA. Novel missense and frameshift mutations in the activin receptor-like kinase-1 gene in hereditary hemorrhagic telangiectasia. Mutations in brief no. 164. Online. Hum Mutat. 1998;12(2):137. PMID:10694922 doi:<137::AID-HUMU16>3.0.CO;2-J 10.1002/(SICI)1098-1004(1998)12:2<137::AID-HUMU16>3.0.CO;2-J
- ↑ Abdalla SA, Pece-Barbara N, Vera S, Tapia E, Paez E, Bernabeu C, Letarte M. Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2. Hum Mol Genet. 2000 May 1;9(8):1227-37. PMID:10767348
- ↑ Kjeldsen AD, Brusgaard K, Poulsen L, Kruse T, Rasmussen K, Green A, Vase P. Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families. Am J Med Genet. 2001 Feb 1;98(4):298-302. PMID:11170071
- ↑ Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, Simonneau G, Galie N, Loyd JE, Humbert M, Nichols WC, Morrell NW, Berg J, Manes A, McGaughran J, Pauciulo M, Wheeler L. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001 Aug 2;345(5):325-34. PMID:11484689 doi:10.1056/NEJM200108023450503
- ↑ Harrison RE, Flanagan JA, Sankelo M, Abdalla SA, Rowell J, Machado RD, Elliott CG, Robbins IM, Olschewski H, McLaughlin V, Gruenig E, Kermeen F, Halme M, Raisanen-Sokolowski A, Laitinen T, Morrell NW, Trembath RC. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet. 2003 Dec;40(12):865-71. PMID:14684682
- ↑ Lesca G, Plauchu H, Coulet F, Lefebvre S, Plessis G, Odent S, Riviere S, Leheup B, Goizet C, Carette MF, Cordier JF, Pinson S, Soubrier F, Calender A, Giraud S. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004 Apr;23(4):289-99. PMID:15024723 doi:10.1002/humu.20017
- ↑ Kuehl HK, Caselitz M, Hasenkamp S, Wagner S, El-Harith el-HA, Manns MP, Stuhrmann M. Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations. Hum Mutat. 2005 Mar;25(3):320. PMID:15712270 doi:10.1002/humu.9311
- ↑ Mahlawat P, Ilangovan U, Biswas T, Sun LZ, Hinck AP. Structure of the Alk1 extracellular domain and characterization of its bone morphogenetic protein (BMP) binding properties. Biochemistry. 2012 Aug 14;51(32):6328-41. Epub 2012 Aug 2. PMID:22799562 doi:10.1021/bi300942x
- ↑ Townson SA, Martinez-Hackert E, Greppi C, Lowden P, Sako D, Liu J, Ucran JA, Liharska K, Underwood KW, Seehra J, Kumar R, Grinberg AV. Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex. J Biol Chem. 2012 Jun 20. PMID:22718755 doi:10.1074/jbc.M112.377960
- ↑ Mazerbourg S, Sangkuhl K, Luo CW, Sudo S, Klein C, Hsueh AJ. Identification of receptors and signaling pathways for orphan bone morphogenetic protein/growth differentiation factor ligands based on genomic analyses. J Biol Chem. 2005 Sep 16;280(37):32122-32. doi: 10.1074/jbc.M504629200. Epub 2005, Jul 27. PMID:16049014 doi:http://dx.doi.org/10.1074/jbc.M504629200
- ↑ David L, Mallet C, Mazerbourg S, Feige JJ, Bailly S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood. 2007 Mar 1;109(5):1953-61. doi: 10.1182/blood-2006-07-034124. Epub 2006, Oct 26. PMID:17068149 doi:http://dx.doi.org/10.1182/blood-2006-07-034124
- ↑ Ye L, Bokobza S, Li J, Moazzam M, Chen J, Mansel RE, Jiang WG. Bone morphogenetic protein-10 (BMP-10) inhibits aggressiveness of breast cancer cells and correlates with poor prognosis in breast cancer. Cancer Sci. 2010 Oct;101(10):2137-44. doi: 10.1111/j.1349-7006.2010.01648.x. Epub, 2010 Jul 1. PMID:20608934 doi:http://dx.doi.org/10.1111/j.1349-7006.2010.01648.x
- ↑ Salmon RM, Guo J, Wood JH, Tong Z, Beech JS, Lawera A, Yu M, Grainger DJ, Reckless J, Morrell NW, Li W. Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms. Nat Commun. 2020 Apr 1;11(1):1621. doi: 10.1038/s41467-020-15425-3. PMID:32238803 doi:http://dx.doi.org/10.1038/s41467-020-15425-3
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