Paper Citing NAMD - Abstract
Vanacore, Roberto M.; Ham, Amy-Joan L.; Cartailler, Jean-Philippe; Sundaramoorthy, Munirathinam; Todd, Parvin; Pedchenko, Vadim; Sado, Yoshikazu; Borza, Dorin-Bogdan; Hudson, Billy G.
A role for collagen IV cross-links in conferring immune privilege to the Goodpasture autoantigen - Structural basis for the crypticity of B cell epitopes
JOURNAL OF BIOLOGICAL CHEMISTRY, 283:22737-22748, AUG 15 2008
The detailed structural basis for the cryptic nature (crypticity) of a B cell epitope harbored by an autoantigen is unknown. Because the immune system may be ignorant of the existence of such " cryptic" epitopes, their exposure could be an important feature in autoimmunity. Here we investigated the structural basis for the crypticity of the epitopes of the Goodpasture autoantigen, the alpha 3 alpha 4 alpha 5 noncollagenous-1 (NC1) hexamer, a globular domain that connects two triple-helical molecules of the alpha 3 alpha 4 alpha 5 collagen IV network. The NC1 hexamer occurs in two isoforms as follows: the M-isoform composed of monomer subunits in which the epitopes are accessible to autoantibodies, and the D-isoform composed of both monomer and dimer subunits in which the epitopes are cryptic. The D-isoform was characterized with respect to quaternary structure, as revealed by mass spectrometry of dimer subunits, homology modeling, and molecular dynamics simulation. The results revealed that the D-isoform contains two kinds of cross-links as follows: S-hydroxylysylmethionine and S-lysyl-methionine cross-links, which stabilize the alpha 3 alpha 5 heterodimers and alpha 4 alpha 4-homodimers, respectively. Construction and analysis of a three-dimensional model of the D-isoform of the alpha 3 alpha 4 alpha 5 NC1 hexamer revealed that crypticity is a consequence of the following: (a) sequestration of key residues between neighboring subunits that are stabilized by domain-swapping interactions, and (b) by cross-linking of subunits at the trimer-trimer interface, which stabilizes the structural integrity of the NC1 hexamer and protects against binding of autoantibodies. The sequestrated epitopes and crosslinked subunits represent a novel structural mechanism for conferring immune privilege at the level of quaternary structure. Perturbation of the quaternary structure may be a key factor in the etiology of Goodpasture disease.
