Molecular recognition of S-nitrosothiol substrate by its cognate protein denitrosylase
| Autor: | Colin T. Stomberski, Hua-Lin Zhou, Liwen Wang, Focco van den Akker, Jonathan S. Stamler |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification 030102 biochemistry & molecular biology Molecular model Mutagenesis HEK 293 cells Cell Biology S-Nitrosylation Biochemistry Small molecule Cell biology 03 medical and health sciences 030104 developmental biology Enzyme Molecular recognition chemistry Molecular Biology Function (biology) |
| Zdroj: | Journal of Biological Chemistry. 294:1568-1578 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra118.004947 |
| Popis: | Protein S-nitrosylation mediates a large part of nitric oxide's influence on cellular function by providing a fundamental mechanism to control protein function across different species and cell types. At steady state, cellular S-nitrosylation reflects dynamic equilibria between S-nitrosothiols (SNOs) in proteins and small molecules (low-molecular-weight SNOs) whose levels are regulated by dedicated S-nitrosylases and denitrosylases. S-Nitroso-CoA (SNO-CoA) and its cognate denitrosylases, SNO-CoA reductases (SCoRs), are newly identified determinants of protein S-nitrosylation in both yeast and mammals. Because SNO-CoA is a minority species among potentially thousands of cellular SNOs, SCoRs must preferentially recognize this SNO substrate. However, little is known about the molecular mechanism by which cellular SNOs are recognized by their cognate enzymes. Using mammalian cells, molecular modeling, substrate-capture assays, and mutagenic analyses, we identified a single conserved surface Lys (Lys-127) residue as well as active-site interactions of the SNO group that mediate recognition of SNO-CoA by SCoR. Comparing SCoRK127A versus SCoRWT HEK293 cells, we identified a SNO-CoA–dependent nitrosoproteome, including numerous metabolic protein substrates. Finally, we discovered that the SNO-CoA/SCoR system has a role in mitochondrial metabolism. Collectively, our findings provide molecular insights into the basis of specificity in SNO-CoA–mediated metabolic signaling and suggest a role for SCoR-regulated S-nitrosylation in multiple metabolic processes. |
| Databáze: | OpenAIRE |
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