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Physical Chemistry

Proteins Nitrated At Specific Sites

ACS Meeting News: Approach enables study of the role of α-synuclein nitration in Parkinson’s disease

by Stu Borman
March 30, 2015 | A version of this story appeared in Volume 93, Issue 13

This week’s selections are from the ACS national meeting, which took place on March 22–26 in Denver.

Researchers have developed the first synthetic method to substitute nitrated versions of tyrosine at specific sites in otherwise native proteins. They used the technique to study the effects of replacing tyrosine with 3-nitrotyrosine in α-synuclein, which aggregates to form fibrils in the brains of Parkinson’s disease patients. α-Synuclein has four tyrosines, and nitration of some of them may help lead to neurodegeneration by promoting fibril formation. Existing techniques to control tyrosine nitration have limited specificity, making it difficult to study such phenomena. Hilal A. Lashuel and coworkers at ETH Lausanne reported using solid-phase peptide synthesis, native chemical ligation, and a new desulfurization technique to nitrate one or more tyrosines in α-synuclein site-specifically (J. Am. Chem. Soc. 2015, DOI: 10.1021/ja5131726). This enabled them to study the effects of tyrosine nitration on α-synuclein structure, oligomerization, and fibril formation. The approach also will facilitate the development of antibodies and imaging agents to detect and quantify α-synuclein species that form aggregates in the brains of Parkinson’s patients, Lashuel said.

Scheme showing amino-acid ranges of a protein having their tyrosines selectively nitrated.
Credit: J. Am. Chem. Soc.
In fragments of the 140-amino acid protein α-synuclein (α-syn), researchers modify fragment termini to accommodate native chemical ligation (NCL). They also substitute one or more tyrosines (Y) with 3-nitrotyrosines (nY). NCL combines the fragments. Desulfurization then converts residues at fragment connection points back to native alanines. Numbers represent residue/fragment sequence positions/ranges, and R is an organic functional group.


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