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A portion of human complement factor H spanning the 15th (H15) and 16th (H16) of
its 20 modules, has been expressed in a yeast vector and subjected to structure
determination in solution using two-dimensional 1H-NMR. The structure of H15 is
very similar to that already established for the fifth module of factor H and
H16, consistent with the view that all such complement control (C-) modules
share a common overall topology. In addition, the tertiary structures of the
component modules of the H15-16 pair are very similar to those of the modules
when expressed individually, implying that each folds entirely autonomously
within intact factor H. Aromatic residues in the third turn of H15 and the
second turn of H16, together with a leucine residue from the linker region,
contribute to a small intermodular interface. Comparatively few nuclear
Overhauser effects were observable between protons on different modules.
Consequently, a wide range of angles of "twist" (131 (+/- 146) degrees, mean
value (+/- 1 standard deviation)), i.e. rotation about the long axis of one
module with respect to the other, exists in the family of structures generated
on the basis of the experimental data. However, much smaller variations occur in
the two, orthogonal, angles (175 (+/- 12) degrees and 103 (+/- 6) degrees) that
describe the "tilt". These observations may suggest upper limits on the relative
flexibility of the two modules. Models were built to assess the outcome of
applying such restrictions to all the neighbours within a string of 20
C-modules, and the resulting structures compare well with factor H as visualized
by electron microscopy.
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