Inhibitor-binding mode of homobelactosin C to proteasomes: new insights into class I MHC ligand generation.
Most class I MHC ligands are generated from the vast majority of cellular proteins by proteolysis within the ubiquitin-proteasome pathway and are presented on the cell surface by MHC class I molecules. Here, we present the crystallographic analysis of yeast 20S proteasome in complex with the inhibitor homobelactosin C. The structure reveals a unique inhibitor-binding mode and provides information about the composition of proteasomal primed substrate-binding sites. IFN-gamma inducible substitution of proteasomal constitutive subunits by immunosubunits modulates characteristics of generated peptides, thus producing fragments with higher preference for binding to MHC class I molecules. The structural data for the proteasome:homobelactosin C complex provide an explanation for involvement of immunosubunits in antigen generation and open perspectives for rational design of ligands, inhibiting exclusively constitutive proteasomes or immunoproteasomes.
Ludwig Maximilians Universität, Adolf Butenandt Institut, Butenandtstrasse 5, Gebäude B, D-81377 Munich, Germany. mgroll@med.uni-muenchen.de
Michael
M
Groll
Oleg V
OV
Larionov
Robert
R
Huber
Armin
A
de Meijere
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D008024:Ligands; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D021122:Protein Subunits / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000201:enzymology*
D015853:Cysteine Proteinase Inhibitors; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D010455:Peptides; D021122:Protein Subunits; C406054:belactosin C; D046988:Proteasome Endopeptidase Complex