Factor H family proteins: on complement, microbes and human diseases

Area of Science:

• Immunology
• Proteomics
• Genetics

Background:

• The human Factor H protein family comprises seven multifunctional serum proteins, including Factor H, Factor H-like protein 1 (FHL-1), and five Factor H-related proteins (FHR-1 to -5).
• These proteins are composed of short consensus repeats (SCRs) or complement control modules, with distinct functional domains.
• Previous studies localized the complement regulatory domain of Factor H and FHL-1 to the N-terminal SCRs 1-4.

Purpose of the Study:

• To elucidate the structure-function relationships within the Factor H protein family.
• To identify key domains involved in protein interactions and their clinical relevance.
• To investigate the role of specific Factor H domains in diseases like hemolytic uremic syndrome.

Main Methods:

• Structure-function analyses were employed to map protein domains and binding sites.
• Comparative analysis of Factor H and FHR proteins identified conserved domains.
• Genetic mutation analysis in patients with Factor H-associated hemolytic uremic syndrome was performed.

Main Results:

• Complement regulatory activity of Factor H and FHL-1 is primarily located in the N-terminal SCRs 1-4.
• Multiple binding sites for C3b, heparin, and microbial proteins are distributed across the N-terminus, middle, and C-terminus.
• The C-terminal region (SCRs 19-20) is highly conserved among FHRs and serves as a critical interaction site, identified as a 'hot-spot' for mutations in hemolytic uremic syndrome.

Conclusions:

• The C-terminus of Factor H, specifically SCRs 19-20, plays a pivotal role in protein interactions and is implicated in Factor H-associated diseases.
• Understanding the domain organization and function of the Factor H family is crucial for comprehending complement regulation and associated pathologies.
• Targeting conserved domains may offer therapeutic strategies for Factor H-related disorders.