PDBsum entry 2kms

Immune system

PDB id: 2kms

Contents

Protein chain

115 a.a. *

* Residue conservation analysis

PDB id:

2kms

Name:

Immune system

Title:

Combined high- and low-resolution techniques reveal compact structure in central portion of factor h despite long inter-modular linkers

Structure:

Complement factor h. Chain: a. Fragment: sushi domain, residues 690-804. 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:

20 models

Authors:

C.Q.Schmidt,A.P.Herbert,M.Guariento,H.D.T.Mertens,D.C.Soares,D.Uhrin, A.J.Rowe,D.I.Svergun,P.N.Barlow

Key ref:

C.Q.Schmidt et al. (2010). The Central Portion of Factor H (Modules 10-15) Is Compact and Contains a Structurally Deviant CCP Module. J Mol Biol, 395, 105-122. PubMed id: 19835885 DOI: 10.1016/j.jmb.2009.10.010

Date:

04-Aug-09 Release date: 03-Nov-09

Protein chain

P08603  (CFAH_HUMAN) -  Complement factor H from Homo sapiens

Seq: 1231 a.a.

Struc: 115 a.a.

DOI no: 10.1016/j.jmb.2009.10.010

J Mol Biol 395:105-122 (2010)

PubMed id: 19835885

The Central Portion of Factor H (Modules 10-15) Is Compact and Contains a Structurally Deviant CCP Module.

C.Q.Schmidt, A.P.Herbert, H.D.Mertens, M.Guariento, D.C.Soares, D.Uhrin, A.J.Rowe, D.I.Svergun, P.N.Barlow.

ABSTRACT

The first eight and the last two of 20 complement control protein (CCP) modules within complement factor H (fH) encompass binding sites for C3b and polyanionic carbohydrates. These binding sites cooperate self-surface selectively to prevent C3b amplification, thus minimising complement-mediated damage to host. Intervening fH CCPs, apparently devoid of such recognition sites, are proposed to play a structural role. One suggestion is that the generally small CCPs 10-15, connected by longer-than-average linkers, act as a flexible tether between the two functional ends of fH; another is that the long linkers induce a 180 degrees bend in the middle of fH. To test these hypotheses, we determined the NMR-derived structure of fH12-13 consisting of module 12, shown here to have an archetypal CCP structure, and module 13, which is uniquely short and features a laterally protruding helix-like insertion that contributes to a prominent electropositive patch. The unusually long fH12-13 linker is not flexible. It packs between the two CCPs that are not folded back on each other but form a shallow vee shape; analytical ultracentrifugation and X-ray scattering supported this finding. These two techniques additionally indicate that flanking modules (within fH11-14 and fH10-15) are at least as rigid and tilted relative to neighbours as are CCPs 12 and 13 with respect to one another. Tilts between successive modules are not unidirectional; their principal axes trace a zigzag path. In one of two arrangements for CCPs 10-15 that fit well with scattering data, CCP 14 is folded back onto CCP 13. In conclusion, fH10-15 forms neither a flexible tether nor a smooth bend. Rather, it is compact and has embedded within it a CCP module (CCP 13) that appears to be highly specialised given both its deviant structure and its striking surface charge distribution. A passive, purely structural role for this central portion of fH is unlikely.

Selected figure(s)

Figure 5.
Fig. 5. Comparisons of CCPs 12 and 13 with a set of known CCP structures. Cartoon representations (PyMOL) of CCPs 12 and 13 flank a C^α trace overlay (generated using the program MAMMOTH-mult^19) of all CCPs with experimentally derived three-dimensional structures from the complement system. Highlighted within the overlay are CCP 12 (red) and CCP 13 (blue).

Figure 6.
Fig. 6. Illustrations of the electrostatic surface and intermodular interface of fH12–13. (a) Electrostatic surface^43 (top; same view as in Fig. 3e); CCP 12 is predominantly electronegative, whilst the linker and CCP 13 display an electropositive patch that includes the helix-like hypervariable region. (b) In this cartoon (PyMOL), disulphides are drawn as sticks (yellow sulphur atoms), CCP 12 is shown in red, CCP 13 is shown in blue, and linker is shown in yellow/orange. Different shades of these colours are used to distinguish side chains (drawn as spheres; heavy atoms only) contributing to the intermodular interface. Side chains are labelled in the blow-up (bottom).

The above figures are reprinted by permission from Elsevier: J Mol Biol (2010, 395, 105-122) copyright 2010.

Figures were selected by an automated process.