D. Chamberlain et al., POSSIBLE ARRANGEMENT OF THE 5 DOMAINS IN HUMAN-COMPLEMENT FACTOR-I ASDETERMINED BY A COMBINATION OF X-RAY AND NEUTRON-SCATTERING AND HOMOLOGY MODELING, Biochemistry (Easton), 37(40), 1998, pp. 13918-13929
Human factor I is a multidomain plasma serine protease with one factor
I-membrane attack complex (FIMAC) domain, one CD5 domain, two low-den
sity lipoprotein receptor (LDLr) domains, and one serine protease (SP)
domain and is essential for the regulation of complement. The domain
arrangement in factor I was determined by X-ray and neutron scattering
on serum-derived human factor I (sFI) and recombinant insect cell fac
tor I (rFI). While the radii of gyration of both were the same at 4.05
nm and both had overall lengths of 14 nm, the cross-sectional radii o
f gyration were different at 1.70 nm for sFI and 1.57 nm for rFI. This
difference was attributed to their different means of glycosylation w
hich is complex-type for sFI and high-mannose-type for rFI. Homology m
odels were constructed for the FIMAC, LDLr, and SP domains of factor I
using related crystal structures, and CD5 was represented as a globul
ar protein by referencing its electron microscopy dimensions. In these
models, 38 of the 40 Cys residues in factor I were predicted to form
internal disulfide bridges. The two remaining Cys residues at the N te
rminus of the FIMAC domain and at the center of the first LDLr domain
were potentially not bridged. It was postulated that, if these two Cys
residues were bridged to each other, the FIMAC, CD5, and LDLr-1 domai
ns would form a compact triangular arrangement. This hypothesis was te
sted by automated scattering curve fit searches based on 9600 bilobal
models, setting the FIMAC, CD5, and LDLr-1 domains as one lobe and the
large SP domain as the other lobe. The searches gave a single small f
amily of similar structures with a separation of 5.9 nm between the ce
nters of the lobes which gave similar good X-ray and neutron fits for
both sFI and rFI, despite the different glycosylations of sFI and rFI.
These best-fit structures for factor I showed that this domain model
is plausible, and suggested that the SP and the CD5 and LDLr-1 domains
may present exposed surfaces in factor I whose roles are to interact
separately with its substrates C3b and C4b and with cofactor proteins.