Human C3 glomerulopathy provides unique insights into complement factor H–related protein function
V. Michael Holers
V. Michael Holers
Published June 3, 2013
Citation Information: J Clin Invest. 2013;123(6):2357-2360. https://doi.org/10.1172/JCI69684.
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Category: Commentary

Human C3 glomerulopathy provides unique insights into complement factor H–related protein function

Abstract

The study in this issue of the JCI by Tortajada et al. demonstrates that a duplication within the gene complement factor H–related 1 (CFHR1; encoding FHR1) leads to the production of an aberrant larger form of the protein. Elegant in vitro studies of the mutant and normal variants demonstrate an unexpected mechanism of action of FHR1, wherein homodimeration and hetero-oligomerization with FHR2 and FHR5 generates more avid molecules that very effectively compete with FH binding to surfaces and impair its ability to regulate local complement activation. As variants of FHRs are linked to many human inflammatory and autoimmune diseases, these and other recently published structure/function studies of these proteins provide key insights into their complement regulatory activities and likely roles in disease.

Authors

V. Michael Holers

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Figure 1

Postulated roles for FHRs based on the current reports discussed herein (8, 18) as well as previous studies (reviewed in refs.

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Postulated roles for FHRs based on the current reports discussed herein ...
9, 10, 12). Deregulation is manifest by FHR1, FHR2, and FHR5 when these oligomerize and compete with FH for C3b binding. Activities of FHR3 and FHR4A/B are less well defined, but may vary by the context in which they are used. Green color of the C-terminal 2 SCR domains of the FHRs indicates a very high degree of sequence similarity (>90%) with FH SCR19–SCR20. Other domains exhibit lower degrees of homology with FH, but three of the family members (FHR1, FHR2, and FHR5) exhibit conserved dimerization domains (18). The FH regulatory complex model is based on data reported and summarized elsewhere (21): the primary interaction with C3b requires SCR19, and the interaction with GAG occurs within SCR20.