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System-wide identification and prioritization of enzyme substrates by thermal analysis

Saei, Amir Ata ; Beusch, Christian M ; Sabatier, Pierre ; Wells, Juan Astorga ; Gharibi, Hassan ; Meng, Zhaowei ; Chernobrovkin, Alexey ; Rodin, Sergey ; Näreoja, Katja and Thorsell, Ann-Gerd , et al. (2021) In Nature Communications 12(1).
Abstract

Despite the immense importance of enzyme-substrate reactions, there is a lack of general and unbiased tools for identifying and prioritizing substrate proteins that are modified by the enzyme on the structural level. Here we describe a high-throughput unbiased proteomics method called System-wide Identification and prioritization of Enzyme Substrates by Thermal Analysis (SIESTA). The approach assumes that the enzymatic post-translational modification of substrate proteins is likely to change their thermal stability. In our proof-of-concept studies, SIESTA successfully identifies several known and novel substrate candidates for selenoprotein thioredoxin reductase 1, protein kinase B (AKT1) and poly-(ADP-ribose) polymerase-10 systems.... (More)

Despite the immense importance of enzyme-substrate reactions, there is a lack of general and unbiased tools for identifying and prioritizing substrate proteins that are modified by the enzyme on the structural level. Here we describe a high-throughput unbiased proteomics method called System-wide Identification and prioritization of Enzyme Substrates by Thermal Analysis (SIESTA). The approach assumes that the enzymatic post-translational modification of substrate proteins is likely to change their thermal stability. In our proof-of-concept studies, SIESTA successfully identifies several known and novel substrate candidates for selenoprotein thioredoxin reductase 1, protein kinase B (AKT1) and poly-(ADP-ribose) polymerase-10 systems. Wider application of SIESTA can enhance our understanding of the role of enzymes in homeostasis and disease, opening opportunities to investigate the effect of post-translational modifications on signal transduction and facilitate drug discovery.

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publishing date
type
Contribution to journal
publication status
published
keywords
Carcinoma, Drug Discovery, Enzymes/chemistry, HCT116 Cells, Humans, Mass Spectrometry, Poly(ADP-ribose) Polymerases/chemistry, Protein Processing, Post-Translational, Proteins/chemistry, Proteomics/methods, Proto-Oncogene Proteins/chemistry, Proto-Oncogene Proteins c-akt/chemistry, Substrate Specificity, Thioredoxin Reductase 1/chemistry
in
Nature Communications
volume
12
issue
1
article number
1296
pages
13 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85101778668
  • pmid:33637753
ISSN
2041-1723
DOI
10.1038/s41467-021-21540-6
language
English
LU publication?
no
id
f8f0c30a-98b3-4bf6-9423-d7c88d4b3c0e
date added to LUP
2024-11-21 17:44:21
date last changed
2025-07-05 12:24:26
@article{f8f0c30a-98b3-4bf6-9423-d7c88d4b3c0e,
  abstract     = {{<p>Despite the immense importance of enzyme-substrate reactions, there is a lack of general and unbiased tools for identifying and prioritizing substrate proteins that are modified by the enzyme on the structural level. Here we describe a high-throughput unbiased proteomics method called System-wide Identification and prioritization of Enzyme Substrates by Thermal Analysis (SIESTA). The approach assumes that the enzymatic post-translational modification of substrate proteins is likely to change their thermal stability. In our proof-of-concept studies, SIESTA successfully identifies several known and novel substrate candidates for selenoprotein thioredoxin reductase 1, protein kinase B (AKT1) and poly-(ADP-ribose) polymerase-10 systems. Wider application of SIESTA can enhance our understanding of the role of enzymes in homeostasis and disease, opening opportunities to investigate the effect of post-translational modifications on signal transduction and facilitate drug discovery.</p>}},
  author       = {{Saei, Amir Ata and Beusch, Christian M and Sabatier, Pierre and Wells, Juan Astorga and Gharibi, Hassan and Meng, Zhaowei and Chernobrovkin, Alexey and Rodin, Sergey and Näreoja, Katja and Thorsell, Ann-Gerd and Karlberg, Tobias and Cheng, Qing and Lundström, Susanna L and Gaetani, Massimiliano and Végvári, Ákos and Arnér, Elias S J and Schüler, Herwig and Zubarev, Roman A}},
  issn         = {{2041-1723}},
  keywords     = {{Carcinoma; Drug Discovery; Enzymes/chemistry; HCT116 Cells; Humans; Mass Spectrometry; Poly(ADP-ribose) Polymerases/chemistry; Protein Processing, Post-Translational; Proteins/chemistry; Proteomics/methods; Proto-Oncogene Proteins/chemistry; Proto-Oncogene Proteins c-akt/chemistry; Substrate Specificity; Thioredoxin Reductase 1/chemistry}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{System-wide identification and prioritization of enzyme substrates by thermal analysis}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-21540-6}},
  doi          = {{10.1038/s41467-021-21540-6}},
  volume       = {{12}},
  year         = {{2021}},
}