bi9805184_si_001.pdf (257.92 kB)
Possible Arrangement of the Five Domains in Human Complement Factor I As Determined by a Combination of X-ray and Neutron Scattering and Homology Modeling
journal contribution
posted on 1998-09-18, 00:00 authored by Dean Chamberlain, Christopher G. Ullman, Stephen J. PerkinsHuman factor I is a multidomain plasma serine protease with one factor I−membrane attack
complex (FIMAC) domain, one CD5 domain, two low-density 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 factor 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 of 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 which is
complex-type for sFI and high-mannose-type for rFI. Homology models were constructed for the FIMAC,
LDLr, and SP domains of factor I using related crystal structures, and CD5 was represented as a globular
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
terminus 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
domains would form a compact triangular arrangement. This hypothesis was tested 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 family of similar
structures with a separation of 5.9 nm between the centers 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.