2rlq

From Proteopedia

Revision as of 16:37, 20 March 2008

NMR structure of CCP modules 2-3 of complement factor H

Overview

Factor H is a regulatory glycoprotein of the complement system. We expressed the three N-terminal complement control protein modules of human factor H (FH[1-3]) and confirmed FH[1-3] to be the minimal unit with cofactor activity for C3b proteolysis by factor I. We reconstructed FH[1-3] from NMR-derived structures of FH[1-2] and FH[2-3] revealing an ~105-A 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; 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 Val62 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) Arg53 by His (an atypical hemolytic uremic syndrome-linked mutation) did not impair structural integrity at 37 degrees C, but this FH[1-2] mutant was less stable at higher temperatures; furthermore, chemical shift differences indicated potential for small structural changes at the module 1-2 interface.

About this Structure

2RLQ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations., Hocking HG, Herbert AP, Kavanagh D, Soares DC, Ferreira VP, Pangburn MK, Uhrin D, Barlow PN, J Biol Chem. 2008 Feb 5;. PMID:18252712

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