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Recognition of enzymes lacking bound cofactor by protein quality control

October 2016. Newly synthetized enzymes must fold correctly and associate with cofactors to reach their functional state. Frankfurt scientists led by Martin Vabulas have now demonstrated that cofactor deprivation due to vitamin B2 deficiency results in destabilization of a significant fraction of flavin-containing enzymes, even if they have wild-type sequences. The accumulation of conditionally unstable proteins would overload cellular protein degradation systems. Consequently, these proteins would contribute to amyloidogenesis and protein aggregation disorders. Since nutritional deficits often develop in aging organisms, the connection between vitamin supplies and healthy aging receives an additional, protein stability-based explanation with this study.

The contribution of cellular protein quality control (PQC) machinery to enzyme maturation remains largely unexplored, although loading of a cofactor represents an all-or-nothing transition in regard to the enzymatic function and thus must be carefully surveyed. Combining proteomics and biochemical analysis, the scientists showed how cells can detect functionally immature wild-type enzymes. The PQC-dedicated ubiquitin ligase CHIP recognizes and marks for degradation not only a mutant protein, but also its wild-type variant as long as the latter remains cofactor-free. A distinct structural feature, the protruding C-terminal tail contributes to the recognition by CHIP. These results, which have just been published in the Proceedings of the National Academy of Sciences of the U.S.A. suggest novel means for therapeutic intervention to stabilize aging and aggregating proteomes. More...

R. Martin Vabulas, Buchmann Institute of Molecular Life Sciences and Institute of Biophysical Chemistry, Goethe-University Frankfurt, Germany, vabulas@em.uni-frankfurt.de

Martínez-Limón A., Alriquet M., Lang W.-H., Calloni G., Wittig I., Vabulas R.M. Recognition of enzymes lacking bound cofactor by protein quality control. PNAS 2016 ; published online ahead of print October 12, 2016, doi:10.1073/pnas.1611994113. Link