Solution structure of CCP modules 10-12 illuminates functional architecture of the complement regulator, factor H

Area of Science:

• Biochemistry
• Structural Biology
• Immunology

Background:

• Factor H (FH) is a 155-kDa plasma glycoprotein composed of 20 complement control protein (CCP) modules.
• FH protects host tissues from complement-mediated damage by interacting with specific host surface fragments.
• The structural and functional roles of CCP modules 9-18 in FH are not well understood.

Purpose of the Study:

• To elucidate the three-dimensional structure of CCP modules 10-12 and 10-13 of Factor H.
• To investigate the structural arrangement and flexibility of CCP modules 8-15 of Factor H.
• To understand the implications of these structures for the complement regulatory mechanism of FH.

Main Methods:

• High-resolution solution structures of overlapping recombinant CCP pairs (10-11, 11-12) were determined.
• Structures were concatenated to form a 3D model of CCPs 10-12.
• Small-angle X-ray scattering (SAXS) was used to validate the structures and analyze longer recombinant FH fragments (CCPs 10-15, 8-15).

Main Results:

• A three-dimensional structure of CCPs 10-12 was determined, and an S-shaped structure for CCPs 10-13 was resolved.
• Modules within CCPs 10-13 exhibit significant tilting (80-110°), with a distinct bend between CCPs 10 and 11.
• SAXS data analysis suggested flexible attachment of CCPs 8-9 to CCP 10, but compact arrangements involving CCP 14 with CCPs 12, 13, and 15.

Conclusions:

• The structure of CCPs 10-13 reveals a unique S-shaped conformation with specific inter-module angles.
• Difficulties in producing certain recombinant CCP pairs (13-14, 14-15) and aberrant CCP 13 structure suggest a dependency of CCP 14 on its neighboring modules.
• These findings provide crucial structural insights into the FH mechanism of complement regulation.