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2qcq
From Proteopedia
| 2qcq, resolution 2.21Å () | |||||||||
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| Gene: | BMP3 (Homo sapiens) | ||||||||
| Domains: | TGFB | ||||||||
| Related: | 2qcw | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Crystal structure of Bone Morphogenetic Protein-3 (BMP-3)
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.
BMP-3 and BMP-6 structures illuminate the nature of binding specificity with receptors., Allendorph GP, Isaacs MJ, Kawakami Y, Belmonte JC, Choe S, Biochemistry. 2007 Oct 30;46(43):12238-47. Epub 2007 Oct 9. PMID:17924656
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
2QCQ is a 2 chains structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- Allendorph GP, Isaacs MJ, Kawakami Y, Belmonte JC, Choe S. BMP-3 and BMP-6 structures illuminate the nature of binding specificity with receptors. Biochemistry. 2007 Oct 30;46(43):12238-47. Epub 2007 Oct 9. PMID:17924656 doi:10.1021/bi700907k
Page seeded by OCA on Tue Feb 17 17:23:52 2009
