2QCQ

Crystal structure of Bone Morphogenetic Protein-3 (BMP-3)

2QCQ の概要

• エントリーDOI: 10.2210/pdb2qcq/pdb
• 関連するPDBエントリー: 2QCW
• 分子名称: Bone morphogenetic protein 3 (2 entities in total)
• 機能のキーワード: bmp, tgf-beta, signaling protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted: P12645
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 24836.86

構造登録者

Allendorph, G.P. (登録日: 2007-06-19, 公開日: 2007-10-23, 最終更新日: 2024-11-06)

主引用文献

Allendorph, G.P.,Isaacs, M.J.,Kawakami, Y.,Belmonte, J.C.,Choe, S.
BMP-3 and BMP-6 Structures Illuminate the Nature of Binding Specificity with Receptors.
Biochemistry, 46:12238-12247, 2007

PubMed Abstract: Bone morphogenetic proteins (BMPs) are extracellular messenger ligands involved in controlling a wide array of developmental and intercellular signaling processes. To initiate their specific intracellular signaling pathways, the ligands recognize and bind two structurally related serine/threonine kinase receptors, termed type I and type II, on the cell surface. Here, we present the crystal structures of BMP-3 and BMP-6, of which BMP-3 has remained poorly understood with respect to its receptor identity, affinity, and specificity. Using surface plasmon resonance (BIAcore) we show that BMP-3 binds Activin Receptor type II (ActRII) with Kd approximately 1.8 microM but ActRIIb with 30-fold higher affinity at Kd approximately 53 nM. This low affinity for ActRII may involve Ser-28 and Asp-33 of BMP-3, which are found only in BMP-3's type II receptor-binding interfaces. Point mutations of either residue to alanine results in up to 20-fold higher affinity to either receptor. We further demonstrate by Smad-based whole cell luciferase assays that the increased affinity of BMP-3S28A to ActRII enables the ligand's signaling ability to a level comparable to that of BMP-6. Focusing on BMP-3's preference for ActRIIb, we find that Lys-76 of ActRII and the structurally equivalent Glu-76 of ActRIIb are distinct between the two receptors. We demonstrate that ActRIIbE76K and ActRII bind BMP-3 with similar affinity, indicating BMP-3 receptor specificity is controlled by the interaction of Lys-30 of BMP-3 with Glu-76 of ActRIIb. These studies illustrate how a single amino acid can regulate the specificity of ligand-receptor binding and potentially alter biological signaling and function in vivo.

PubMed: 17924656
DOI: 10.1021/bi700907k

実験手法

X-RAY DIFFRACTION (2.21 Å)