Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10.
Authors
Liu, Bin
Thorikay, Midory
Li, Xiaoyan
Tong, Zhen
Ten Dijke, Peter
Publication Date
2022-05-03Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Springer Science and Business Media LLC
Volume
13
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
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
Abstract
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.
Keywords
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
Sponsorship
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)
Identifiers
s41467-022-30111-2, 30111
External DOI: https://doi.org/10.1038/s41467-022-30111-2
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336826
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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