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Analysis of binding sites on complement factor I that are required for its activity.

In English

Författare

Summary, in English

The central complement inhibitor factor I (FI) degrades activated complement factors C4b and C3b in the presence of cofactors such as C4b-binding protein, factor H, complement receptor 1 and membrane cofactor protein. FI is a serine protease composed of two chains; the light chain comprises the serine protease domain, while the heavy chain contains several domains: the FI and membrane attack complex domain (FIMAC), CD5, low density lipoprotein receptor 1 (LDLr1) and LDLr2 domains. In order to understand better how FI acts as a complement inhibitor, we used homology-based models of FI domains to predict potential binding sites. Specific amino acids were then mutated to yield 16 well-expressed mutants, which were then purified from media of eukaryotic cells for functional analyses. The Michaelis constant (Km) of all FI mutants towards a small substrate was not altered while some mutants showed increased maximum initial velocity (Vmax). All the mutations in the FIMAC domain affected the ability of FI to degrade C4b and C3b irrespective of the cofactor used whereas only some mutations in the CD5 and LDLr1/2 domains had similar effect. These same mutants also showed impaired binding to C3met. In conclusion, the FIMAC domain appears to harbor the main binding sites important for the ability of FI to degrade C4b and C3b.

Avdelning/ar

Publiceringsår

2010

Språk

Engelska

Sidor

6235-6245

Publikation/Tidskrift/Serie

Journal of Biological Chemistry

Volym

285

Dokumenttyp

Artikel i tidskrift

Förlag

American Society for Biochemistry and Molecular Biology

Ämne

  • Medicinal Chemistry

Status

Published

Forskningsgrupp

  • Clinical Chemistry, Malmö
  • Protein Chemistry, Malmö
  • Chronic Inflammatory and Degenerative Diseases Research Unit

ISBN/ISSN/Övrigt

  • ISSN: 1083-351X