Solution structure of the fifth repeat of factor H: a second example of the complement control protein module

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Complement control protein (CCP) modules are assumed to share structural features based on consensus sequences.
• Previous determination of the 3D structure of human factor H, H16 (a CCP module) provided a reference point.

Purpose of the Study:

• To determine the three-dimensional structure of a second CCP module, human factor H, H5.
• To compare the structural features of H5 with H16 to assess the influence of the consensus sequence on protein structure.

Main Methods:

• Utilized a combination of two-dimensional Nuclear Magnetic Resonance (2D NMR) spectroscopy.
• Employed simulated annealing techniques for structure determination.
• Compared the determined structure of H5 with the previously resolved structure of H16.

Main Results:

• The three-dimensional structure of H5 was successfully determined.
• H5 shares extensive similarities in secondary structure with H16, suggesting the consensus sequence dictates secondary structure.
• While tertiary structures are broadly similar (hydrophobic core, beta-strands/sheets), H5 exhibits minor differences including a deletion and insertion, leading to a rearranged hydrophobic core and altered positioning of conserved residues like Tyr29.

Conclusions:

• The consensus sequence plays a significant role in defining the secondary structure of CCP modules.
• Despite minor sequence variations (deletions/insertions), CCP modules maintain overall structural resemblance, indicating a conserved fold.
• The study reinforces the principle that conserved sequences often correlate with conserved protein structures.