Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10.
Ten Dijke, Peter
Springer Science and Business Media LLC
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Guo, J., Liu, B., Thorikay, M., Yu, M., Li, X., Tong, Z., Salmon, R. M., et al. (2022). Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10.. Nat Commun, 13 (1) https://doi.org/10.1038/s41467-022-30111-2
Heterozygous 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 β4 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.
Article, /631/45/127/1219, /631/80/86/2368, /631/443/592/75/593, /631/535/1266, /101, /82/103, /96/21, /145, /13/95, /82/83, article
British Heart Foundation (None)
British Heart Foundation (PG/17/1/32532)
British Heart Foundation (FS/SBSRF/20/31005)
British Heart Foundation (FS/4yPhD/F/20/34124B)
British Heart Foundation (PG/17/58/33134)
Wellcome Trust (209407/Z/17/Z)
National Institute for Health Research (NIHRDH-IS-BRC-1215-20014)
External DOI: https://doi.org/10.1038/s41467-022-30111-2
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336826