title: Crystal structure analysis reveals a spring-loaded latch as molecular mechanism for GDF-5-type I receptor specificity.
abstract: Dysregulation of growth and differentiation factor 5 (GDF-5) signalling, a member of the TGF-beta superfamily, is strongly linked to skeletal malformation. GDF-5-mediated signal transduction involves both BMP type I receptors, BMPR-IA and BMPR-IB. However, mutations in either GDF-5 or BMPR-IB lead to similar phenotypes, indicating that in chondrogenesis GDF-5 signalling seems to be exclusively mediated through BMPR-IB. Here, we present structural insights into the GDF-5:BMPR-IB complex revealing how binding specificity for BMPR-IB is generated on a molecular level. In BMPR-IB, a loop within the ligand-binding epitope functions similar to a latch allowing high-affinity binding of GDF-5. In BMPR-IA, this latch is in a closed conformation leading to steric repulsion. The new structural data now provide also a molecular basis of how phenotypically relevant missense mutations in GDF-5 might impair receptor binding and activation.
authors.affiliation: Lehrstuhl für Botanik I-Molekulare Pflanzenphysiologie und Biophysik, Julius-von-Sachs-Institut für Biowissenschaften (Biozentrum) der Universität Würzburg, Würzburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kotzsch
authors.forename: Joachim
authors.initials: J
authors.lastname: Nickel
authors.forename: Axel
authors.initials: A
authors.lastname: Seher
authors.forename: Walter
authors.initials: W
authors.lastname: Sebald
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Müller
mesh_terms: D001665:Binding Sites; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D055428:Growth Differentiation Factor 5 / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D012680:Sensitivity and Specificity
chemical_list: D055428:Growth Differentiation Factor 5; D052005:Bone Morphogenetic Protein Receptors, Type I