View the Current Issue

Article

  • The EMBO Journal (2003) 22, 2348 - 2359
  • doi:10.1093/emboj/cdg236

Crystal structure of the CUB1-EGF-CUB2 region of mannose-binding protein associated serine protease-2

Hadar Feinberg1,3, Joost C.M. Uitdehaag2,3, Jason M. Davies1, Russell Wallis2, Kurt Drickamer2 and William I. Weis2

  1. Departments of Structural Biology and of Molecular and Cellular Physiology, Stanford University School of Medicine, 299 Campus Drive West, Stanford, CA 94305-5126, USA
  2. Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
  3. H.Feinberg and J.C.M.Uitdehaag contributed equally to this work

Correspondence to:

William I. Weis, E-mail: bill.weis@stanford.edu

Received 28 January 2003; Accepted 19 March 2003; Revised 18 March 2003

Serum mannose-binding proteins (MBPs) are C-type lectins that recognize cell surface carbohydrate structures on pathogens, and trigger killing of these targets by activating the complement pathway. MBPs circulate as a complex with MBP-associated serine proteases (MASPs), which become activated upon engagement of a target cell surface. The minimal functional unit for complement activation is a MASP homodimer bound to two MBP trimeric subunits. MASPs have a modular structure consisting of an N-terminal CUB domain, a Ca2+-binding EGF-like domain, a second CUB domain, two complement control protein modules and a C-terminal serine protease domain. The CUB1-EGF-CUB2 region mediates homodimerization and binding to MBP. The crystal structure of the MASP-2 CUB1-EGF-CUB2 dimer reveals an elongated structure with a prominent concave surface that is proposed to be the MBP-binding site. A model of the full six-domain structure and its interaction with MBPs suggests mechanisms by which binding to a target cell transmits conformational changes from MBP to MASP that allow activation of its protease activity.

  • Keywords:

    • complement,
    • C1 complex,
    • mannose-binding protein,
    • MASP