Structural Basis of Interaction between Urokinase-type Plasminogen Activator and its Receptor

Cyril Barinka, Graham Parry, Jennifer Callahan, David E. Shaw, Alice Kuo, Khalil Bdeir, Douglas B. Cines, Andrew Mazar, Jacek Lubkowski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

Recent studies indicate that binding of the urokinase-type plasminogen activator (uPA) to its high-affinity receptor (uPAR) orchestrates uPAR interactions with other cellular components that play a pivotal role in diverse (patho-)physiological processes, including wound healing, angiogenesis, inflammation, and cancer metastasis. However, notwithstanding the wealth of biochemical data available describing the activities of uPAR, little is known about the exact mode of uPAR/uPA interactions or the presumed conformational changes that accompany uPA/uPAR engagement. Here, we report the crystal structure of soluble urokinase plasminogen activator receptor (suPAR), which contains the three domains of the wild-type receptor but lacks the cell-surface anchoring sequence, in complex with the amino-terminal fragment of urokinase-type plasminogen activator (ATF), at the resolution of 2.8 Å. We report the 1.9 Å crystal structure of free ATF. Our results provide a structural basis, represented by conformational changes induced in uPAR, for several published biochemical observations describing the nature of uPAR/uPA interactions and provide insight into mechanisms that may be responsible for the cellular responses induced by uPA binding.

Original languageEnglish (US)
Pages (from-to)482-495
Number of pages14
JournalJournal of Molecular Biology
Volume363
Issue number2
DOIs
StatePublished - Oct 20 2006

Keywords

  • X-ray crystallography
  • kringle domain
  • plasminogen
  • protein/protein interactions
  • urokinase receptor

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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