Proteomic data and structure analysis combined reveal interplay of structural rigidity and flexibility on selectivity of cysteine cathepsins

Addressing the elusive specificity of cysteine cathepsins, which in contrast to caspases and trypsin-like proteases lack strict specificity determining P1 pocket, calls for innovative approaches. Proteomic analysis of cell lysates with human cathepsins K, V, B, L, S, and F identified 30,000 cleavage...

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Published in:Communications biology 2023-04, Vol.6 (1), p.450-450, Article 450
Main Authors: Tušar, Livija, Loboda, Jure, Impens, Francis, Sosnowski, Piotr, Van Quickelberghe, Emmy, Vidmar, Robert, Demol, Hans, Sedeyn, Koen, Saelens, Xavier, Vizovišek, Matej, Mihelič, Marko, Fonović, Marko, Horvat, Jaka, Kosec, Gregor, Turk, Boris, Gevaert, Kris, Turk, Dušan
Format: Article
Language:English
Subjects:
101/58
631/154
631/45/468
Biology
Biomedical and Life Sciences
Cathepsins
COVID-19
Crystal structure
Cysteine
Drug development
Humans
Learning algorithms
Life Sciences
Lysates
Machine learning
Proteomics
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
Substrate specificity
Trypsin
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Summary:Addressing the elusive specificity of cysteine cathepsins, which in contrast to caspases and trypsin-like proteases lack strict specificity determining P1 pocket, calls for innovative approaches. Proteomic analysis of cell lysates with human cathepsins K, V, B, L, S, and F identified 30,000 cleavage sites, which we analyzed by software platform SAPS-ESI (Statistical Approach to Peptidyl Substrate-Enzyme Specific Interactions). SAPS-ESI is used to generate clusters and training sets for support vector machine learning. Cleavage site predictions on the SARS-CoV-2 S protein, confirmed experimentally, expose the most probable first cut under physiological conditions and suggested furin-like behavior of cathepsins. Crystal structure analysis of representative peptides in complex with cathepsin V reveals rigid and flexible sites consistent with analysis of proteomics data by SAPS-ESI that correspond to positions with heterogeneous and homogeneous distribution of residues. Thereby support for design of selective cleavable linkers of drug conjugates and drug discovery studies is provided. Proteomics analysis, machine learning, and crystal structures reveal the substrate specificity of cysteine cathepsins.
ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-023-04772-8