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J. Biol. Chem., Vol. 283, Issue 14, 9475-9487, April 4, 2008

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Structure of the N-terminal Region of Complement Factor H and Conformational Implications of Disease-linked Sequence Variations^*

Henry G. Hocking, Andrew P. Herbert, David Kavanagh¹, Dinesh C. Soares, Viviana P. Ferreira^¶, Michael K. Pangburn^¶, Dusan Uhrín, and Paul N. Barlow²

From the Edinburgh Biomolecular NMR Unit, Schools of Chemistry and Biological Sciences, Joseph Black Chemistry Bldg., University of Edinburgh, West Mains Rd., Edinburgh EH9 3JJ, United Kingdom, Medical Genetics Section, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Crewe Rd., Edinburgh EH4 2XU, United Kingdom, and ^¶Department of Biochemistry, Center for Biomedical Research, University of Texas Health Science Center, Tyler, Texas 75708

Factor H is a regulatory glycoprotein of the complement system. We expressed the three N-terminal complement control protein modules of human factor H (FH1-3) and confirmed FH1-3 to be the minimal unit with cofactor activity for C3b proteolysis by factor I. We reconstructed FH1-3 from NMR-derived structures of FH1-2 and FH2-3 revealing an 105-Å-long rod-like arrangement of the modules. In structural comparisons with other C3b-engaging proteins, factor H module 3 most closely resembles factor B module 3, consistent with factor H competing with factor B for binding C3b. Factor H modules 1, 2, and 3 each has a similar backbone structure to first, second, and third modules, respectively, of functional sites in decay accelerating factor and complement receptor type 1; the equivalent intermodular tilt and twist angles are also broadly similar. Resemblance between molecular surfaces is closest for first modules but absent in the case of second modules. Substitution of buried Val-62 with Ile (a factor H single nucleotide polymorphism potentially protective for age-related macular degeneration and dense deposit disease) causes rearrangements within the module 1 core and increases thermal stability but does not disturb the interface with module 2. Replacement of partially exposed (in module 1) Arg-53 by His (an atypical hemolytic uremic syndrome-linked mutation) did not impair structural integrity at 37 °C, but this FH1-2 mutant was less stable at higher temperatures; furthermore, chemical shift differences indicated potential for small structural changes at the module 1-2 interface.

Received for publication, November 26, 2007 , and in revised form, January 18, 2008.

The atomic coordinates and structure factors (codes 2RLP and 2RLQ) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the Medical Research Council and Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-5.

¹ A Kidney Research UK Training Fellow.

³ Author's Choice—Final version full access.

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² To whom correspondence should be addressed. Tel.: 44-0-131-650-4727; Fax: 44-0-131-650-7155; E-mail: Paul.Barlow{at}ed.ac.uk.

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