2G7I

Structure of Human Complement Factor H Carboxyl Terminal Domains 19-20: a Basis for Atypical Hemolytic Uremic Syndrome

Summary for 2G7I

• Entry DOI: 10.2210/pdb2g7i/pdb
• Descriptor: Complement factor H (2 entities in total)
• Functional Keywords: sushi (ccp/scr) domain, complement, regulator, factor h, beta-1h globulin, immune system, atypical hemolytic uremic syndrome, heparin binding
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P08603
• Total number of polymer chains: 1
• Total formula weight: 14297.31

Authors

Jaakola, V.-P.,Jokiranta, T.S.,Goldman, A. (deposition date: 2006-02-28, release date: 2006-05-23, Last modification date: 2024-10-30)

Primary citation

Jokiranta, T.S.,Jaakola, V.-P.,Lehtinen, M.J.,Parepalo, M.,Meri, S.,Goldman, A.
Structure of complement factor H carboxyl-terminus reveals molecular basis of atypical haemolytic uremic syndrome.
Embo J., 25:1784-1794, 2006

PubMed Abstract: Factor H (FH) is the key regulator of the alternative pathway of complement. The carboxyl-terminal domains 19-20 of FH interact with the major opsonin C3b, glycosaminoglycans, and endothelial cells. Mutations within this area are associated with atypical haemolytic uremic syndrome (aHUS), a disease characterized by damage to endothelial cells, erythrocytes, and kidney glomeruli. The structure of recombinant FH19-20, solved at 1.8 A by X-ray crystallography, reveals that the short consensus repeat domain 20 contains, unusually, a short alpha-helix, and a patch of basic residues at its base. Most aHUS-associated mutations either destabilize the structure or cluster in a unique region on the surface of FH20. This region is close to, but distinct from, the primary heparin-binding patch of basic residues. By mutating five residues in this region, we show that it is involved, not in heparin, but in C3b binding. Therefore, the majority of the aHUS-associated mutations on the surface of FH19-20 interfere with the interaction between FH and C3b. This obviously leads to impaired control of complement attack on plasma-exposed cell surfaces in aHUS.

PubMed: 16601698
DOI: 10.1038/sj.emboj.7601052

Experimental method

X-RAY DIFFRACTION (1.75 Å)