Protein degradation by human 20S proteasomes elucidates the interplay between peptide hydrolysis and splicing.

Autor: Soh WT; Research Group of Quantitative and Systems Biology, Max-Planck-Institute for Multidisciplinary Sciences, 37077, Göttingen, Germany., Roetschke HP; Research Group of Quantitative and Systems Biology, Max-Planck-Institute for Multidisciplinary Sciences, 37077, Göttingen, Germany.; Centre for Inflammation Biology and Cancer Immunology & Peter Gorer Department of Immunobiology, King's College London, SE1 1UL, London, UK.; Research Group of Molecular Immunology, Francis Crick Institute, NW1 1AT, London, UK., Cormican JA; Research Group of Quantitative and Systems Biology, Max-Planck-Institute for Multidisciplinary Sciences, 37077, Göttingen, Germany., Teo BF; Centre for Inflammation Biology and Cancer Immunology & Peter Gorer Department of Immunobiology, King's College London, SE1 1UL, London, UK.; Research Group of Molecular Immunology, Francis Crick Institute, NW1 1AT, London, UK.; Immunology Programme, Life Sciences Institute; Immunology Translational Research Program and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore., Chiam NC; Research Group of Quantitative and Systems Biology, Max-Planck-Institute for Multidisciplinary Sciences, 37077, Göttingen, Germany., Raabe M; Research Group of Bioanalytical Mass Spectrometry, Max-Planck-Institute for Multidisciplinary Sciences, 37077, Göttingen, Germany., Pflanz R; Research Group of Bioanalytical Mass Spectrometry, Max-Planck-Institute for Multidisciplinary Sciences, 37077, Göttingen, Germany., Henneberg F; Department of Structural Dynamics, Max-Planck-Institute for Multidisciplinary Sciences, 37077, Göttingen, Germany., Becker S; Department of NMR-based Structural Biology, Max-Planck-Institute for Multidisciplinary Sciences, 37077, Göttingen, Germany., Chari A; Research Group of Structural Biochemistry and Mechanisms, Max-Planck-Institute for Multidisciplinary Sciences, 37077, Göttingen, Germany., Liu H; Immunology Programme, Life Sciences Institute; Immunology Translational Research Program and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore., Urlaub H; Research Group of Bioanalytical Mass Spectrometry, Max-Planck-Institute for Multidisciplinary Sciences, 37077, Göttingen, Germany.; Institute of Clinical Chemistry, University Medical Center Göttingen, 37075, Göttingen, Germany., Liepe J; Research Group of Quantitative and Systems Biology, Max-Planck-Institute for Multidisciplinary Sciences, 37077, Göttingen, Germany. jliepe@mpinat.mpg.de., Mishto M; Centre for Inflammation Biology and Cancer Immunology & Peter Gorer Department of Immunobiology, King's College London, SE1 1UL, London, UK. michele.mishto@kcl.ac.uk.; Research Group of Molecular Immunology, Francis Crick Institute, NW1 1AT, London, UK. michele.mishto@kcl.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Feb 07; Vol. 15 (1), pp. 1147. Date of Electronic Publication: 2024 Feb 07.
DOI: 10.1038/s41467-024-45339-3
Abstrakt: If and how proteasomes catalyze not only peptide hydrolysis but also peptide splicing is an open question that has divided the scientific community. The debate has so far been based on immunopeptidomics, in vitro digestions of synthetic polypeptides as well as ex vivo and in vivo experiments, which could only indirectly describe proteasome-catalyzed peptide splicing of full-length proteins. Here we develop a workflow-and cognate software - to analyze proteasome-generated non-spliced and spliced peptides produced from entire proteins and apply it to in vitro digestions of 15 proteins, including well-known intrinsically disordered proteins such as human tau and α-Synuclein. The results confirm that 20S proteasomes produce a sizeable variety of cis-spliced peptides, whereas trans-spliced peptides are a minority. Both peptide hydrolysis and splicing produce peptides with well-defined characteristics, which hint toward an intricate regulation of both catalytic activities. At protein level, both non-spliced and spliced peptides are not randomly localized within protein sequences, but rather concentrated in hotspots of peptide products, in part driven by protein sequence motifs and proteasomal preferences. At sequence level, the different peptide sequence preference of peptide hydrolysis and peptide splicing suggests a competition between the two catalytic activities of 20S proteasomes during protein degradation.
(© 2024. The Author(s).)
Databáze: MEDLINE
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