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Huber E.M.,TU Munich | Basler M.,University of Konstanz | Basler M.,University of Constance | Schwab R.,University of Konstanz | And 5 more authors.
Cell | Year: 2012

Constitutive proteasomes and immunoproteasomes shape the peptide repertoire presented by major histocompatibility complex class I (MHC-I) molecules by harboring different sets of catalytically active subunits. Here, we present the crystal structures of constitutive proteasomes and immunoproteasomes from mouse in the presence and absence of the epoxyketone inhibitor PR-957 (ONX 0914) at 2.9 resolution. Based on our X-ray data, we propose a unique catalytic feature for the immunoproteasome subunit β5i/LMP7. Comparison of ligand-free and ligand-bound proteasomes reveals conformational changes in the S1 pocket of β5c/X but not β5i, thereby explaining the selectivity of PR-957 for β5i. Time-resolved structures of yeast proteasome:PR-957 complexes indicate that ligand docking to the active site occurs only via the reactive head group and the P1 side chain. Together, our results support structure-guided design of inhibitory lead structures selective for immunoproteasomes that are linked to cytokine production and diseases like cancer and autoimmune disorders. © 2012 Elsevier Inc. Source


Henn A.,University of Konstanz | Basler M.,University of Constance | Guillaume B.,Ludwig Institute for Cancer Research | Leist M.,University of Konstanz | And 2 more authors.
Journal of Immunology | Year: 2010

Tissue inflammation is accompanied by the cytokine-mediated replacement of constitutive proteasomes by immunoproteasomes that finally leads to an optimized generation of MHC class I restricted epitopes for Ag presentation. The brain is considered an immunoprivileged organ, where both the special anatomy as well as active tolerance mechanisms repress the development of inflammatory responses and help to prevent immunopathological damage. We analyzed the immunoproteasome expression in the brain after an infection with lymphocytic choriomeningitis virus (LCMV) and could show that LCMV-infection of mice leads to the transcriptional induction of inducible proteasome subunits in the brain. However, compared with other organs, i.p. and even intracranial infection with LCMV only led to a faint expression of mature immunoproteasome in the brain and resulted in the accumulation of immunoproteasomal precursors. By immunohistology, we could identify microglia-like cells as the main producers of immunoproteasome, whereas in astrocytes immunoproteasome expression was almost exclusively restricted to nuclei. Neither the immunoproteasome subunits low molecular mass polypeptide 2 nor multicatalytic endopeptidase complex-like-1 were detected in neurons or oligodendrocytes. In vitro studies of IFN-γ-stimulated primary astrocytes suggested that the observed accumulation of immunoproteasomal precursor complexes takes place in this cell population. Functionally, the lack of immunoproteasomes protracted and lowered the severity of LCMV-induced meningitis in LMP7-/- mice suggesting a contribution of immunoproteasomes in microglia to exacerbate immunopathological damage. We postulate a posttranslationally regulated mechanism that prevents abundant and inappropriate immunoproteasome assembly in the brain and may contribute to the protection of poorly regenerating cells of the CNS from immunopathological destruction. Copyright © 2010 by The American Association of Immunologists, Inc. Source


Hiller N.,Karlsruhe Institute of Technology | Hillenbrand S.,Karlsruhe Institute of Technology | Hofmann A.,Karlsruhe Institute of Technology | Huttel E.,Karlsruhe Institute of Technology | And 11 more authors.
IPAC 2010 - 1st International Particle Accelerator Conference | Year: 2010

A dedicated optics with a low momentum compaction factor is used at the ANKA storage ring to reduce the bunch length to generate coherent synchrotron radiation (CSR). A double sweep streak camera is employed to determine the bunch length and shape for different optics and as a function of the beam current. Measurements of the longitudinal bunch profile have been performed for many different momentum compaction factors and various bunch currents. This paper describes the set up of the streak camera experiments and compares the measured bunch lengths to theoretical expectations. Source


Rani N.,University of Konstanz | Aichem A.,University of Constance | Schmidtke G.,University of Konstanz | Kreft S.G.,University of Konstanz | And 2 more authors.
Nature Communications | Year: 2012

FAT10 is the only ubiquitin-like modifier that can target proteins for degradation by the proteasome in a ubiquitin-independent manner. The degradation of FAT10-linked proteins by the proteasome is strongly accelerated by the ubiquitin-like-ubiquitin-associated protein NEDD8 ultimate buster-1 long (NUB1L). Here we show how FAT10 and NUB1L dock with the 26S proteasome to initiate proteolysis. We identify the 26S proteasome subunit hRpn10/S5a as the receptor for FAT10, whereas NUB1L can bind to both Rpn10 and Rpn1/S2. Unexpectedly, FAT10 and NUB1L both interact with hRpn10 via the VWA domain. FAT10 degradation in yeast shows that human Rpn10 can functionally reconstitute Rpn10-deficient yeast and that the VWA domain of hRpn10 suffices to enable FAT10 degradation. Depletion of hRpn10 causes an accumulation of FAT10-conjugates also in human cells. In conclusion, we identify the VWA domain of hRpn10 as a receptor for ubiquitin-like proteins within the 26S proteasome and elucidate how FAT10 mediates efficient proteolysis by the proteasome. © 2012 Macmillan Publishers Limited. All rights reserved. Source

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