PDBsum entry 2rlp

Immune system

PDB id: 2rlp

Contents

Protein chain

123 a.a. *

* Residue conservation analysis

PDB id:

2rlp

Name:

Immune system

Title:

Nmr structure of ccp modules 1-2 of complement factor h

Structure:

Complement factor h. Chain: a. Fragment: residues in database 20-142. Synonym: h factor 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cfh, hf, hf1, hf2. Expressed in: pichia pastoris. Expression_system_taxid: 4922.

NMR struc:

30 models

Authors:

H.G.Hocking,A.P.Herbert,M.K.Pangburn,D.Kavanagh,P.N.Barlow,D.Uhrin

Key ref:

H.G.Hocking et al. (2008). Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations. J Biol Chem, 283, 9475-9487. PubMed id: 18252712 DOI: 10.1074/jbc.M709587200

Date:

28-Jul-07 Release date: 19-Feb-08

Protein chain

P08603  (CFAH_HUMAN) -  Complement factor H from Homo sapiens

Seq: 1231 a.a.

Struc: 123 a.a.

DOI no: 10.1074/jbc.M709587200

J Biol Chem 283:9475-9487 (2008)

PubMed id: 18252712

Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations.

H.G.Hocking, A.P.Herbert, D.Kavanagh, D.C.Soares, V.P.Ferreira, M.K.Pangburn, D.Uhrín, P.N.Barlow.

ABSTRACT

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 approximately 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; 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 degrees 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.

Selected figure(s)

Figure 2.
FIGURE 2. NMR-derived structures of FH1-2 and FH2-3 and reconstructed FH1-3. A, backbone representations showing separate ensembles of FH1-2 (cyan) and FH2-3 (magenta) structures, each superimposed on the C[ ]atoms of their respective CCP 2s. B, backbone representations showing both the ensembles superposed on their mutual CCP 2s (C[ ]r.m.s.d. 0.78 Å). C, schematic representation of the structure of FH1-3 derived from structures of overlapping pairs and showing the boundaries of the FH1-2 and FH2-3 structures used as templates in Modeler 9v1 (55, 56). D, orthogonal view of the schematic representation in C.

Figure 5.
FIGURE 5. Comparison of electrostatic surfaces of FH1-3 with DAF-(1-4) (A) and CR1-(15-17) (B). The surfaces were generated using the Adaptive Poisson-Boltzmann Solver (78) plug-in within PyMol (using the PARSE (79) parameter set with the nonlinear form of the Poisson-Boltzmann equation, a protein dielectric constant of 20, solvent dielectric constant of 80, solvent ion radius of 1.4 Å, temperature 310 K, and assumed ion concentration of 100 mM). Red is negative charge, and blue is positive charge within a range of -5/+5kT(k = Boltzmann's constant, T = absolute temperature). The orientation of FH1-3 is the same as in Fig. 2D. The other structures were orientated by superposing DAF CCP 2 (A) or CR1 CCP 15 (B) on FH CCP 1 and then transposing.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2008, 283, 9475-9487) copyright 2008.

Figures were selected by an automated process.