Determination of the solution structure of free human secretory component.

Blaise CORTHESY, Clémentine PERRIER (to September 2008), IAL-CHUV, in collaboration with:
Steven PERKINS and Alexandra BONNER, Department of Biochemistry, University College London, London, U.K.

Secretory component (SC) in association with polymeric IgA (pIgA) forms secretory IgA (SIgA), the major antibody active at mucosal surfaces. SC results from the cleavage of the polymeric Ig receptor (pIgR) that ensures transport of polymeric antibodies into secretions at mucosal surfaces. SC consists of five immunoglobulin-like domains (D1-D5) and up to seven glycan chains.

SC bound to pIgA protects the antibody against proteolytic digestion (6), and governs anchoring of SIgA at mucosal surfaces. Free SC is also found in secretions and is now recognized as an active antibacterial participant to protect mucosal surfaces against Helicobacter pylori, enteropathogenic Escherichia coli and Clostridium difficile toxin A and Streptococcus pneumoniae choline binding protein A.

Despite the importance of SC and its glycosylation, only partial information is available on its structure. SC comprises the first 585 residues in pIgR.

Homology modelling of rabbit SC domains 1 and 2 (D1 and D2) indicates that both exhibit the typical features of Ig variable (V)-type superfamily members with seven -strands A-G and an extra two designated C’ and C’’. A similar topology was determined in the modelling of domains 2 and 3 (D2 and D3) of mouse SC. These were confirmed by the crystal structure of D1 of human SC which revealed a V-type fold. When the project was initiated, the three-dimensional domain arrangement of full-length SC was unknown, even though this is essential to appreciate molecular mechanisms that are involved in mucosal immunity. Its high glycosylation and the presence of long interdomain linkers suggested that SC may be too flexible to be crystallised intact. In a situation such as this, X-ray and neutron scattering and analytical ultracentrifugation in combination with constrained modelling techniques turned out adequate to reveal the domain arrangement of SC. Our study shows that SC forms a compact domain arrangement, and this structure rationalises many of the biological roles of both free and bound SC.

Best-fit models for SC. The domains D1 to D5 are coloured from blue (N-terminus) to red (C-terminus). The ten best-fit models I to X are shown with D1-D3 in the same orientation, with model I being the very best-fit model of all.

The best-fit model of Figure 8A is rotated by 180o to show the CDR I, II and III peptides in D1 (in pink) and Cys502 in D5 (in yellow).

Reference:

• Bonner A., Perrier C., Corthésy B. and Perkins S.J. Solution structure of human secretory component and implications for biological function. J. Biol. Chem. 2007, 282:16969-16980.

Dernière modification le 13.10.2008 - Impressum - Informations juridiques