title: A structural model of 20S immunoproteasomes: effect of LMP2 codon 60 polymorphism on expression, activity, intracellular localisation and insight into the regulatory mechanisms.
abstract: 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-alpha-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 alpha and beta rings.
authors.affiliation: Department of Experimental Pathology, University of Bologna, via S. Giacomo 14, I-40126 Bologna, Italy. michele.mishto@unibo.it
authors.forename: Michele
authors.initials: M
authors.lastname: Mishto
authors.forename: Aurelia
authors.initials: A
authors.lastname: Santoro
authors.forename: Elena
authors.initials: E
authors.lastname: Bellavista
authors.forename: Richard
authors.initials: R
authors.lastname: Sessions
authors.forename: Kathrin
authors.initials: K
authors.lastname: Textoris-Taube
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Dal Piaz
authors.forename: Geraldine
authors.initials: G
authors.lastname: Carrard
authors.forename: Katia
authors.initials: K
authors.lastname: Forti
authors.forename: Stefano
authors.initials: S
authors.lastname: Salvioli
authors.forename: Bertrand
authors.initials: B
authors.lastname: Friguet
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kloetzel
authors.forename: A Jennifer
authors.initials: AJ
authors.lastname: Rivett
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
mesh_terms: D000911:Antibodies, Monoclonal; D002467:Cell Nucleus / Q000378:metabolism; D003062:Codon; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D008958:Models, Molecular; D011110:Polymorphism, Genetic; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000911:Antibodies, Monoclonal; D003062:Codon; D021122:Protein Subunits; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex