9DPY

BMP-10 with BMP-9 Crystal Contacts

9DPY の概要

• エントリーDOI: 10.2210/pdb9dpy/pdb
• 分子名称: Bone morphogenetic protein 10, PHOSPHATE ION, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: signaling protein, bmp, bone morphogenetic protein, tgf-beta family
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 25606.87

構造登録者

Schwartze, T.A.,Hinck, A.P. (登録日: 2024-09-23, 公開日: 2025-03-05)

主引用文献

Schwartze, T.A.,Morosky, S.A.,Rosato, T.L.,Henrickson, A.,Lin, G.,Hinck, C.S.,Taylor, A.B.,Olsen, S.K.,Calero, G.,Demeler, B.,Roman, B.L.,Hinck, A.P.
Molecular Basis of Interchain Disulfide Bond Formation in BMP-9 and BMP-10.
J.Mol.Biol., 437:168935-168935, 2025

PubMed Abstract: BMP-9 and BMP-10 are TGF-β family signaling ligands naturally secreted into blood. They act on endothelial cells and are required for proper development and maintenance of the vasculature. In hereditary hemorrhagic telangiectasia, regulation is disrupted due to mutations in the BMP-9/10 pathway, namely in the type I receptor ALK1 or the co-receptor endoglin. It has been demonstrated that BMP-9/10 heterodimers are the most abundant signaling species in the blood, but it is unclear how they form. Unlike other ligands of the TGF-β family, BMP-9 and -10 are secreted as a mixture of disulfide-linked dimers and monomers in which the interchain cysteine (Cys-392) remains either unpaired or paired. Here, we show that the monomers are secreted in a cysteinylated form that crystallizes as a non-covalent dimer. Despite this, monomers do not self-associate at micromolar or lower concentrations and have reduced signaling potency compared to disulfide-linked dimers. We further show using protein crystallography that the interchain disulfide of the BMP-9 homodimer adopts a highly strained syn-periplanar conformation. Hence, geometric strain across the interchain disulfide is responsible for infrequent interchain disulfide bond formation, not the cysteinylation. Additionally, we show that interchain disulfide bond formation occurs less in BMP-9 than BMP-10 and these frequencies can be reversed by swapping residues near the interchain disulfide that form attractive interactions with the opposing protomer. Finally, we discuss the implications of these observations on BMP-9/10 heterodimer formation.

PubMed: 39793884
DOI: 10.1016/j.jmb.2025.168935

実験手法

X-RAY DIFFRACTION (1.77 Å)