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High resolution structure of bone morphogenetic protein receptor type II (BMPRII) extracellular domain in complex with BMP10High resolution structure of bone morphogenetic protein receptor type II (BMPRII) extracellular domain in complex with BMP10
Structural highlights
DiseaseBMPR2_HUMAN 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.[1] [2] [3] [4] [5] [6] 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.[7] [8] FunctionBMPR2_HUMAN 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. Publication Abstract from PubMedHeterozygous mutations in BMPR2 (bone morphogenetic protein (BMP) receptor type II) cause pulmonary arterial hypertension. BMPRII is a receptor for over 15 BMP ligands, but why BMPR2 mutations cause lung-specific pathology is unknown. To elucidate the molecular basis of BMP:BMPRII interactions, we report crystal structures of binary and ternary BMPRII receptor complexes with BMP10, which contain an ensemble of seven different BMP10:BMPRII 1:1 complexes. BMPRII binds BMP10 at the knuckle epitope, with the A-loop and beta4 strand making BMPRII-specific interactions. The BMPRII binding surface on BMP10 is dynamic, and the affinity is weaker in the ternary complex than in the binary complex. Hydrophobic core and A-loop interactions are important in BMPRII-mediated signalling. Our data reveal how BMPRII is a low affinity receptor, implying that forming a signalling complex requires high concentrations of BMPRII, hence mutations will impact on tissues with highest BMPR2 expression such as the lung vasculature. Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10.,Guo J, Liu B, Thorikay M, Yu M, Li X, Tong Z, Salmon RM, Read RJ, Ten Dijke P, Morrell NW, Li W Nat Commun. 2022 May 3;13(1):2395. doi: 10.1038/s41467-022-30111-2. PMID:35504921[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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