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.
Feinberg
Hadar
H
Departments of Structural Biology and of Molecular and Cellular Physiology, Stanford University School of Medicine, 299 Campus Drive West, CA 94305-5126, USA.
Uitdehaag
Joost C M
JC
Davies
Jason M
JM
Wallis
Russell
R
Drickamer
Kurt
K
Weis
William I
WI
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