PDBsum entry: 2qcq

Signaling protein

PDB id: 2qcq

Contents

Protein chains

107 a.a. *

Waters ×98

* Residue conservation analysis

PDB id:

2qcq

Name:

Signaling protein

Title:

Crystal structure of bone morphogenetic protein-3 (bmp-3)

Structure:

Bone morphogenetic protein 3. Chain: a, b. Synonym: bmp-3, osteogenin, bmp-3a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bmp3. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.

Resolution:

2.21Å R-factor: 0.230 R-free: 0.257

Authors:

G.P.Allendorph

Key ref:

G.P.Allendorph et al. (2007). BMP-3 and BMP-6 structures illuminate the nature of binding specificity with receptors. Biochemistry, 46, 12238-12247. PubMed id: 17924656 DOI: 10.1021/bi700907k

Date:

19-Jun-07 Release date: 23-Oct-07

Protein chains

P12645  (BMP3_HUMAN) -  Bone morphogenetic protein 3

Seq: 472 a.a.

Struc: 107 a.a.

 Gene Ontology (GO) functional annotation 

• Cellular component: extracellular region (1 term)
• Biochemical function: growth factor activity (1 term)

DOI no: 10.1021/bi700907k

Biochemistry 46:12238-12247 (2007)

PubMed id: 17924656

BMP-3 and BMP-6 structures illuminate the nature of binding specificity with receptors.

G.P.Allendorph, M.J.Isaacs, Y.Kawakami, J.C.Belmonte, S.Choe.

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.