Journal Article/Internal Report

PUBDB-2014-04152

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Nanoscale structure of the BMP antagonist chordin supports cooperative BMP binding

Troilo, H. (Corresponding Author)>Extern* ; Zuk, A. V. ; Tunnicliffe, R. B. ; Wohl, A. P. ; Berry, R. ; Collins, R. F. ; Jowitt, T. A. ; Sengle, G. ; Baldock, C.>Extern*

2014
National Acad. of Sciences Washington, DC

This record in other databases:      

Please use a persistent id in citations: doi:10.1073/pnas.1404166111

Report No.: SAXS-5

Abstract: Bone morphogenetic proteins (BMPs) orchestrate key cellular events, such as proliferation and differentiation, in development and homeostasis. Extracellular antagonists, such as chordin, are essential regulators of BMP signaling. Chordin binds to BMPs blocking interaction with receptors, and cleavage by tolloid proteinases is thought to relieve this inhibition. A model has been previously proposed where chordin adopts a horseshoe-like arrangement enabling BMP binding cooperatively by terminal domains (1). Here, we present the nanoscale structure of human chordin using electron microscopy, small angle X-ray scattering, and solution-based biophysical techniques, which together show that chordin indeed has a compact horseshoe-shaped structure. Chordin variants were used to map domain locations within the chordin molecule. The terminal BMP-binding domains protrude as prongs from the main body of the chordin structure, where they are well positioned to interact with the growth factor. The spacing provided by the chordin domains supports the principle of a cooperative BMP-binding arrangement that the original model implied in which growth factors bind to both an N- and C-terminal von Willebrand factor C domain of chordin. Using binding and bioactivity assays, we compared full-length chordin with two truncated chordin variants, such as those produced by partial tolloid cleavage. Cleavage of either terminal domain has little effect on the affinity of chordin for BMP-4 and BMP-7 but C-terminal cleavage increases the efficacy of chordin as a BMP-4 inhibitor. Together these data suggest that partial tolloid cleavage is insufficient to ablate BMP inhibition and the C-terminal chordin domains play an important role in BMP regulation.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. PETRA Beamline P12 (POF2-54G14) (POF2-54G14)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2014

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Database coverage:
; BIOSIS Previews ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; National-Konsortium ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection ; Zoological Record

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