New structural motifs on the chymotrypsin fold and their potential roles in complement factor B.
Factor B and C2 are two central enzymes for complement activation. They are multidomain serine proteases and require cofactor binding for full expression of proteolytic activities. We present a 2.1 A crystal structure of the serine protease domain of factor B. It shows a number of structural motifs novel to the chymotrypsin fold, which by sequence homology are probably present in C2 as well. These motifs distribute characteristically on the protein surface. Six loops surround the active site, four of which shape substrate-binding pockets. Three loops next to the oxyanion hole, which typically mediate zymogen activation, are much shorter or absent. Three insertions including the linker to the preceding domain bulge from the side opposite to the active site. The catalytic triad and non-specific substrate-binding site display active conformations, but the oxyanion hole displays a zymogen-like conformation. The bottom of the S1 pocket has a negative charge at residue 226 instead of the typical 189 position. These unique structural features may play different roles in domain-domain interaction, cofactor binding and substrate binding.
Jing
H
H
Center for Macromolecular Crystallography, School of Optometry, University of Alabama at Birmingham, 35294, USA.
Xu
Y
Y
Carson
M
M
Moore
D
D
Macon
K J
KJ
Volanakis
J E
JE
Narayana
S V
SV
D000595:Amino Acid Sequence; D001665:Binding Sites; D002918:Chymotrypsin / Q000737:chemistry* / Q000378:metabolism; D002919:Chymotrypsinogen / Q000737:chemistry; D003175:Complement C2 / Q000737:chemistry; D011415:Complement Factor B / Q000737:chemistry* / Q000378:metabolism; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry*
D003175:Complement C2; D011994:Recombinant Proteins; D002919:Chymotrypsinogen; D012697:Serine Endopeptidases; D002918:Chymotrypsin; D011415:Complement Factor B