Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex

Ann Hye Ryong Shim, Heli Liu, Pamela J. Focia, Xiaoyan Chen, P. Charles Lin, Xiaolin He*

*Corresponding author for this work

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are prototypic growth factors and receptor tyrosine kinases which have critical functions in development. We show that PDGFs share a conserved region in their prodomain sequences which can remain noncovalently associated with the mature cystine-knot growth factor domain after processing. The structure of the PDGF-A/propeptide complex reveals this conserved, hydrophobic association mode. We also present the structure of the complex between PDGF-B and the first three Ig domains of PDGFRβ, showing that two PDGF-B protomers clamp PDGFRβ at their dimerization seam. The PDGF-B:PDGFRβ interface is predominantly hydrophobic, and PDGFRs and the PDGF propeptides occupy overlapping positions on mature PDGFs, rationalizing the need of propeptides by PDGFs to cover functionally important hydrophobic surfaces during secretion. A large-scale structural organization and rearrangement is observed for PDGF-B upon receptor binding, in which the PDGF-B L1 loop, disordered in the structure of the free form, adopts a highly specific conformation to form hydrophobic interactions with the third Ig domain of PDGFRβ. Calorimetric data also shows that the membrane-proximal homotypic PDGFRα interaction, albeit required for activation, contributes negatively to ligand binding. The structural and biochemical data together offer insights into PDGF-PDGFR signaling, as well as strategies for PDGF-antagonism.

Original languageEnglish (US)
Pages (from-to)11307-11312
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number25
DOIs
StatePublished - Jun 22 2010

Keywords

  • Crystallography
  • Receptor tyrosine kinase
  • Signal transduction

ASJC Scopus subject areas

  • General

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