Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10

• Main Authors: Guo, J. (Author), Li, W. (Author), Li, X. (Author), Liu, B. (Author), Morrell, N.W (Author), Read, R.J (Author), Salmon, R.M (Author), ten Dijke, P. (Author), Thorikay, M. (Author), Tong, Z. (Author), Yu, M. (Author)
• Format: Article
• Language: English
• Published: Nature Research 2022
• Online Access: View Fulltext in Publisher
• ISBN: 20411723 (ISSN)
• DOI: 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. © 2022, The Author(s).