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Michele Mishto, Aurelia Santoro, Elena Bellavista, Richard Sessions, Kathrin Textoris-Taube, Fabrizio Dal Piaz, Geraldine Carrard, Katia Forti, Stefano Salvioli, Bertrand Friguet, Peter M. Kloetzel, A. Jennifer Rivett, Claudio Franceschi

A structural model of 20S immunoproteasomes: effect of LMP2 codon 60 polymorphism on expression, activity, intracellular localisation and insight into the regulatory mechanisms

Keywords: immunoproteasome, LMP2, Polymorphism, proteasome regulation, structural model

The immunoproteasome subunit low molecular weight protein 2 (LMP2) codon 60 polymorphism has been associated with autoimmune diseases. It has also been demonstrated to influence susceptibility to TNF-?-induced apoptosis in blood cells and proteasome activity in aged human brain. In the present study, an in silico model of immunoproteasome was used to examine the effect of the R60H polymorphism in the LMP2 subunit. The investigation of immunoproteasome expression, activity and intracellular localisation in an in vitro cellular model, namely lymphoblastoid cell lines, showed no major variations in functionality and amount, while a significant difference in antibody affinity was apparent. These data were integrated with previous results obtained in different tissues and combined with a structural model of the LMP2 polymorphism. Accordingly, we identified three prospective mechanisms that could explain the biological data for the polymorphism, such as modulation of the binding affinity of a putative non-catalytic modifier site on the external surface of the immunoproteasome core, or the modification of any channel between ? and ? rings.

Biological Chemistry, Walter de Gruyter

Print ISSN: 1431-6730
Volume: 387, 04/2006
Pages: 417 - 429

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