Crystal structure of the CUB1-EGF-CUB2 region of mannose-binding protein associated serine protease-2.
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 Ca(2+)-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.
Departments of Structural Biology and of Molecular and Cellular Physiology, Stanford University School of Medicine, 299 Campus Drive West, CA 94305-5126, USA.
Hadar
H
Feinberg
Joost C M
JC
Uitdehaag
Jason M
JM
Davies
Russell
R
Wallis
Kurt
K
Drickamer
William I
WI
Weis
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002151:Calorimetry; D006224:Cricetinae; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D037601:Mannose-Binding Lectin / Q000737:chemistry / Q000378:metabolism; D050606:Mannose-Binding Protein-Associated Serine Proteases; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D037601:Mannose-Binding Lectin; C069858:mannose binding protein A; C491340:MASP-2 protein, mouse; D050606:Mannose-Binding Protein-Associated Serine Proteases; C491338:Masp2 protein, rat; D012697:Serine Endopeptidases; D002118:Calcium