Cargando…

Myelin Basic Protein Fragmentation by Engineered Human Proteasomes with Different Catalytic Phenotypes Revealed Direct Peptide Ligands of MS-Associated and Protective HLA Class I Molecules

Proteasomes exist in mammalian cells in multiple combinatorial variants due to the diverse regulatory particles and exchange of catalytic subunits. Here, using biotin carboxyl carrier domain of transcarboxylase from Propionibacterium shermanii fused with different proteasome subunits of catalytic an...

Descripción completa

Detalles Bibliográficos
Autores principales: Saratov, George A., Vladimirov, Vasiliy I., Novoselov, Alexey L., Ziganshin, Rustam H., Chen, Guo, Baymukhametov, Timur N., Konevega, Andrey L., Belogurov, Alexey A., Kudriaeva, Anna A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917034/
https://www.ncbi.nlm.nih.gov/pubmed/36768413
http://dx.doi.org/10.3390/ijms24032091
_version_ 1784886272059244544
author Saratov, George A.
Vladimirov, Vasiliy I.
Novoselov, Alexey L.
Ziganshin, Rustam H.
Chen, Guo
Baymukhametov, Timur N.
Konevega, Andrey L.
Belogurov, Alexey A.
Kudriaeva, Anna A.
author_facet Saratov, George A.
Vladimirov, Vasiliy I.
Novoselov, Alexey L.
Ziganshin, Rustam H.
Chen, Guo
Baymukhametov, Timur N.
Konevega, Andrey L.
Belogurov, Alexey A.
Kudriaeva, Anna A.
author_sort Saratov, George A.
collection PubMed
description Proteasomes exist in mammalian cells in multiple combinatorial variants due to the diverse regulatory particles and exchange of catalytic subunits. Here, using biotin carboxyl carrier domain of transcarboxylase from Propionibacterium shermanii fused with different proteasome subunits of catalytic and regulatory particles, we report comprehensive characterization of highly homogenous one-step purified human constitutive and immune 20S and 26S/30S proteasomes. Hydrolysis of a multiple sclerosis (MS) autoantigen, myelin basic protein (MBP), by engineered human proteasomes with different catalytic phenotypes, revealed that peptides which may be directly loaded on the HLA class I molecules are produced mainly by immunoproteasomes. We detected at least five MBP immunodominant core regions, namely, LPRHRDTGIL, SLPQKSHGR, QDENPVVHFF, KGRGLSLSRF and GYGGRASDY. All peptides, except QDENPVVHFF, which originates from the encephalitogenic MBP part, were associated with HLA I alleles considered to increase MS risk. Prediction of the affinity of HLA class I to this peptide demonstrated that MS-protective HLA-A*44 and -B*35 molecules are high-affinity binders, whereas MS-associated HLA-A*23, -A*24, -A*26 and -B*51 molecules tend to have moderate to low affinity. The HLA-A*44 molecules may bind QDENPVVHFF and its deamidated form in several registers with unprecedently high affinity, probably linking its distinct protective phenotype with thymic depletion of the repertoire of autoreactive cytotoxic T cells or induction of CD8+ regulatory T cells, specific to the encephalitogenic MBP peptide.
format Online
Article
Text
id pubmed-9917034
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-99170342023-02-11 Myelin Basic Protein Fragmentation by Engineered Human Proteasomes with Different Catalytic Phenotypes Revealed Direct Peptide Ligands of MS-Associated and Protective HLA Class I Molecules Saratov, George A. Vladimirov, Vasiliy I. Novoselov, Alexey L. Ziganshin, Rustam H. Chen, Guo Baymukhametov, Timur N. Konevega, Andrey L. Belogurov, Alexey A. Kudriaeva, Anna A. Int J Mol Sci Article Proteasomes exist in mammalian cells in multiple combinatorial variants due to the diverse regulatory particles and exchange of catalytic subunits. Here, using biotin carboxyl carrier domain of transcarboxylase from Propionibacterium shermanii fused with different proteasome subunits of catalytic and regulatory particles, we report comprehensive characterization of highly homogenous one-step purified human constitutive and immune 20S and 26S/30S proteasomes. Hydrolysis of a multiple sclerosis (MS) autoantigen, myelin basic protein (MBP), by engineered human proteasomes with different catalytic phenotypes, revealed that peptides which may be directly loaded on the HLA class I molecules are produced mainly by immunoproteasomes. We detected at least five MBP immunodominant core regions, namely, LPRHRDTGIL, SLPQKSHGR, QDENPVVHFF, KGRGLSLSRF and GYGGRASDY. All peptides, except QDENPVVHFF, which originates from the encephalitogenic MBP part, were associated with HLA I alleles considered to increase MS risk. Prediction of the affinity of HLA class I to this peptide demonstrated that MS-protective HLA-A*44 and -B*35 molecules are high-affinity binders, whereas MS-associated HLA-A*23, -A*24, -A*26 and -B*51 molecules tend to have moderate to low affinity. The HLA-A*44 molecules may bind QDENPVVHFF and its deamidated form in several registers with unprecedently high affinity, probably linking its distinct protective phenotype with thymic depletion of the repertoire of autoreactive cytotoxic T cells or induction of CD8+ regulatory T cells, specific to the encephalitogenic MBP peptide. MDPI 2023-01-20 /pmc/articles/PMC9917034/ /pubmed/36768413 http://dx.doi.org/10.3390/ijms24032091 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Saratov, George A.
Vladimirov, Vasiliy I.
Novoselov, Alexey L.
Ziganshin, Rustam H.
Chen, Guo
Baymukhametov, Timur N.
Konevega, Andrey L.
Belogurov, Alexey A.
Kudriaeva, Anna A.
Myelin Basic Protein Fragmentation by Engineered Human Proteasomes with Different Catalytic Phenotypes Revealed Direct Peptide Ligands of MS-Associated and Protective HLA Class I Molecules
title Myelin Basic Protein Fragmentation by Engineered Human Proteasomes with Different Catalytic Phenotypes Revealed Direct Peptide Ligands of MS-Associated and Protective HLA Class I Molecules
title_full Myelin Basic Protein Fragmentation by Engineered Human Proteasomes with Different Catalytic Phenotypes Revealed Direct Peptide Ligands of MS-Associated and Protective HLA Class I Molecules
title_fullStr Myelin Basic Protein Fragmentation by Engineered Human Proteasomes with Different Catalytic Phenotypes Revealed Direct Peptide Ligands of MS-Associated and Protective HLA Class I Molecules
title_full_unstemmed Myelin Basic Protein Fragmentation by Engineered Human Proteasomes with Different Catalytic Phenotypes Revealed Direct Peptide Ligands of MS-Associated and Protective HLA Class I Molecules
title_short Myelin Basic Protein Fragmentation by Engineered Human Proteasomes with Different Catalytic Phenotypes Revealed Direct Peptide Ligands of MS-Associated and Protective HLA Class I Molecules
title_sort myelin basic protein fragmentation by engineered human proteasomes with different catalytic phenotypes revealed direct peptide ligands of ms-associated and protective hla class i molecules
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917034/
https://www.ncbi.nlm.nih.gov/pubmed/36768413
http://dx.doi.org/10.3390/ijms24032091
work_keys_str_mv AT saratovgeorgea myelinbasicproteinfragmentationbyengineeredhumanproteasomeswithdifferentcatalyticphenotypesrevealeddirectpeptideligandsofmsassociatedandprotectivehlaclassimolecules
AT vladimirovvasiliyi myelinbasicproteinfragmentationbyengineeredhumanproteasomeswithdifferentcatalyticphenotypesrevealeddirectpeptideligandsofmsassociatedandprotectivehlaclassimolecules
AT novoselovalexeyl myelinbasicproteinfragmentationbyengineeredhumanproteasomeswithdifferentcatalyticphenotypesrevealeddirectpeptideligandsofmsassociatedandprotectivehlaclassimolecules
AT ziganshinrustamh myelinbasicproteinfragmentationbyengineeredhumanproteasomeswithdifferentcatalyticphenotypesrevealeddirectpeptideligandsofmsassociatedandprotectivehlaclassimolecules
AT chenguo myelinbasicproteinfragmentationbyengineeredhumanproteasomeswithdifferentcatalyticphenotypesrevealeddirectpeptideligandsofmsassociatedandprotectivehlaclassimolecules
AT baymukhametovtimurn myelinbasicproteinfragmentationbyengineeredhumanproteasomeswithdifferentcatalyticphenotypesrevealeddirectpeptideligandsofmsassociatedandprotectivehlaclassimolecules
AT konevegaandreyl myelinbasicproteinfragmentationbyengineeredhumanproteasomeswithdifferentcatalyticphenotypesrevealeddirectpeptideligandsofmsassociatedandprotectivehlaclassimolecules
AT belogurovalexeya myelinbasicproteinfragmentationbyengineeredhumanproteasomeswithdifferentcatalyticphenotypesrevealeddirectpeptideligandsofmsassociatedandprotectivehlaclassimolecules
AT kudriaevaannaa myelinbasicproteinfragmentationbyengineeredhumanproteasomeswithdifferentcatalyticphenotypesrevealeddirectpeptideligandsofmsassociatedandprotectivehlaclassimolecules