Function-guided proximity mapping unveils electrophilic-metabolite sensing by proteins not present in their canonical locales

Author:

Zhao Yi123,Miranda Herrera Pierre A.12,Chang Dalu12,Hamelin Romain4,Long Marcus J. C.25,Aye Yimon12ORCID

Affiliation:

1. Institute of Chemical Sciences and Engineering, School of Basic Sciences, Swiss Federal Institute of Technology Lausanne, 1015 Lausanne, Switzerland

2. National Centre of Competence in Research Chemical Biology, University of Geneva, 1211 Geneva, Switzerland

3. BayRay Innovation Center, Shenzhen Bay Laboratory, Shenzhen 518055, Guangdong, China

4. Proteomics Core Facility, School of Life Sciences, Swiss Federal Institute of Technology Lausanne, 1015 Lausanne, Switzerland

5. Department of Biochemistry, Faculty of Biology and Medicine, University of Lausanne, 1066 Epalinges, Switzerland

Abstract

Significance The cell is a hive of information flow in which metabolite signals and proteins translocate across subcompartments. Peering into this submicroscopic world is hugely challenging. Using a strategy termed Localis-rex, we identify subcellular locale-specific sensors of a native reactive electrophilic metabolite. Surprisingly, several proteins sense electrophiles in locales where they do not canonically reside. One example is the nuclear protein, CDK9. In the cytosol, the electrophilic-metabolite–modified CDK9 has no negative function. However, following nuclear translocation, the electrophilic-metabolite–modified CDK9 downregulates the transcriptional activator, RNA-Polymerase-II. This exquisitely-nuanced signaling modality highlights the need to assign means, motive, and opportunity to proteins involved in reactive metabolite signaling.

Funder

Swiss National Science Foundation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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