Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10
| Autor: | Guo, Jingxu, Liu, Bin, Thorikay, Midory, Yu, Minmin, Li, Xiaoyan, Tong, Zhen, Salmon, Richard M, Read, Randy, Ten Dijke, Peter, Morrell, Nicholas, Li, Wei |
|---|---|
| Přispěvatelé: | Guo, Jingxu [0000-0002-1568-4842], Yu, Minmin [0000-0003-4442-7586], Salmon, Richard M [0000-0001-6327-5341], Read, Randy J [0000-0001-8273-0047], Morrell, Nicholas W [0000-0001-5700-9792], Li, Wei [0000-0002-1924-3120], Apollo - University of Cambridge Repository, Read, Randy [0000-0001-8273-0047], Morrell, Nicholas [0000-0001-5700-9792] |
| Rok vydání: | 2022 |
| Předmět: |
Pulmonary Arterial Hypertension
Multidisciplinary 101 145 Cell Membrane article General Physics and Astronomy General Chemistry Bone Morphogenetic Protein Receptors Type II Crystallography X-Ray 631/443/592/75/593 96/21 General Biochemistry Genetics and Molecular Biology 631/535/1266 Bone Morphogenetic Proteins 631/45/127/1219 13/95 Humans 631/80/86/2368 82/103 Familial Primary Pulmonary Hypertension 82/83 Signal Transduction |
| Zdroj: | Nature Communications, 13(1). NATURE PORTFOLIO |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-022-30111-2 |
| Popis: | 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 beta 4 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.Mutations in BMPR2 is the major genetic cause for pulmonary arterial hypertension (PAH). Here by solving crystal structures of BMPRII in binary and ternary receptor complexes with BMP10, the authors report the molecular recognition between BMPRII and BMP10, and its implication in PAH. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink