Crystal structure analysis reveals how the Chordin family member crossveinless 2 blocks BMP-2 receptor binding.
Crossveinless 2 (CV-2) is an extracellular BMP modulator protein belonging to the Chordin family. During development it is expressed at sites of high BMP signaling and like Chordin CV-2 can either enhance or inhibit BMP activity. CV-2 binds to BMP-2 via its N-terminal Von Willebrand factor type C (VWC) domain 1. Here we report the structure of the complex between CV-2 VWC1 and BMP-2. The tripartite VWC1 binds BMP-2 only through a short N-terminal segment, called clip, and subdomain (SD) 1. Mutational analysis establishes that the clip segment and SD1 together create high-affinity BMP-2 binding. All four receptor-binding sites of BMP-2 are blocked in the complex, demonstrating that VWC1 acts as competitive inhibitor for all receptor types. In vivo experiments reveal that the BMP-enhancing (pro-BMP) activity of CV-2 is independent of BMP-2 binding by VWC1, showing that pro- and anti-BMP activities are structurally separated in CV-2.
Zhang
Jin-Li
JL
Department of Physiological Chemistry II, Biocenter, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany.
Qiu
Li-Yan
LY
Kotzsch
Alexander
A
Weidauer
Stella
S
Patterson
Lucy
L
Hammerschmidt
Matthias
M
Sebald
Walter
W
Mueller
Thomas D
TD
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D055396:Bone Morphogenetic Protein 2; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000737:chemistry; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000737:chemistry / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D024043:Collagen Type II / Q000737:chemistry; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry; D005353:Fibronectins / Q000737:chemistry; D020690:GTPase-Activating Proteins / Q000737:chemistry* / Q000378:metabolism*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D040681:Structural Homology, Protein; D016212:Transforming Growth Factor beta / Q000737:chemistry* / Q000378:metabolism; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000737:chemistry* / Q000378:metabolism*
D055396:Bone Morphogenetic Protein 2; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins; D024043:Collagen Type II; D000939:Epitopes; D005353:Fibronectins; D020690:GTPase-Activating Proteins; D016212:Transforming Growth Factor beta; D029961:Zebrafish Proteins; C525719:Bmp2 protein, mouse; C509801:crossveinless 2 protein, zebrafish