Domain metastability: a molecular basis for immunoglobulin deposition?
Sonnen AF, Yu C, Evans EJ, Stuart DI, Davis SJ, Gilbert RJ. (2010), J Mol Biol. 399, 207-13
We present the crystal structure of an immunoglobulin light-chain-like domain, CTLA-4, as a strand-swapped dimer displaying cis-trans proline isomerisation and native-like hydrogen bonding. We also show that CTLA-4 can form amyloid-like fibres and amorphous deposits explainable by the same strand swapping. Our results suggest a molecular basis for the pathological aggregation of immunoglobulin domains and why amyloid-like fibres are more often composed of homologous rather than heterologous subunits.
Key figure: Structure of a strand-swapped Ig-domain dimer
The structure of the stand-swapped dimer is shown in (a) and its topological diagram in (b) (strands named according to standard conventions). For comparison, (c) displays the topology diagram of the homodimeric maCTLA-4 ectodomain (Yu et al., manuscript in preparation). The location of the disulfide is shown in yellow. The close-ups are molecular representations of the hinge regions (red boxes) in the swapped (top, carbon in green, oxygen in red, nitrogen in blue and sulfur in yellow) and unswapped (bottom, same colours except carbon in grey) vl-Ig domains. For purification of samples, see Supplementary Fig. S1 and Ref. 19; for structure determination method and statistics for ecCTLA-4, see Table 1. (d) Omit map calculations for the structure. The hinge region of the dimer was omitted in calculation of both the 2Fo − Fc map (blue) and the Fo − Fc map (green, at + 3σ; red at − 3σ). The atomic model for one-half of the crystallographic dimer is included in the figure.