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  4. A Versatile Method for Site-Specific Chemical Installation of Aromatic Posttranslational Modification Analogs into Proteins
 
research article

A Versatile Method for Site-Specific Chemical Installation of Aromatic Posttranslational Modification Analogs into Proteins

Lin, Xiaoxi
•
Mandal, Shaswati  
•
Nithun, Raj V.
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September 18, 2024
Journal of the American Chemical Society

Posttranslational modifications (PTMs) of proteins play central roles in regulating the protein structure, interactome, and functions. A notable modification site is the aromatic side chain of Tyr, which undergoes modifications such as phosphorylation and nitration. Despite the biological and physiological importance of Tyr-PTMs, our current understanding of the mechanisms by which these modifications contribute to human health and disease remains incomplete. This knowledge gap arises from the absence of natural amino acids that can mimic these PTMs and the lack of synthetic tools for the site-specific introduction of aromatic PTMs into proteins. Herein, we describe a facile method for the site-specific chemical installation of aromatic PTMs into proteins through palladium-mediated S-C(sp2) bond formation under ambient conditions. We demonstrate the incorporation of novel PTMs such as Tyr-nitration and phosphorylation analogs to synthetic and recombinantly expressed Cys-containing peptides and proteins within minutes and in good yields. To demonstrate the versatility of our approach, we employed it to prepare 10 site-specifically modified proteins, including nitrated and phosphorylated analogs of Myc and Max proteins. Furthermore, we prepared a focused library of site-specifically nitrated and phosphorylated α-synuclein (α-Syn) protein, which enabled, for the first time, deciphering the role of these competing modifications in regulating α-Syn conformation aggregation in vitro. Our strategy offers advantages over synthetic or semisynthetic approaches, as it enables rapid and selective transfer of rarely explored aromatic PTMs into recombinant proteins, thus facilitating the generation of novel libraries of homogeneous posttranslationally modified proteins for biomarker discovery, mechanistic studies, and drug discovery.

  • Details
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Type
research article
DOI
10.1021/jacs.4c08416
Scopus ID

2-s2.0-85202930640

PubMed ID

39224092

Author(s)
Lin, Xiaoxi

Tel Aviv University

Mandal, Shaswati  

École Polytechnique Fédérale de Lausanne

Nithun, Raj V.

Tel Aviv University

Kolla, Rajasekhar  

École Polytechnique Fédérale de Lausanne

Bouri, Bouchra  

École Polytechnique Fédérale de Lausanne

Lashuel, Hilal A.  

École Polytechnique Fédérale de Lausanne

Jbara, Muhammad

Tel Aviv University

Date Issued

2024-09-18

Published in
Journal of the American Chemical Society
Volume

146

Issue

37

Start page

25788

End page

25798

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
LCBM  
LMNN  
FunderFunding(s)Grant NumberGrant URL

EPFL

Council for Higher Education

Neubauer Foundation

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Available on Infoscience
January 24, 2025
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/243733
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