Department of Biochemistry and Molecular Pharmacology; Program in Chemical Biology; Thompson Lab
Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry
Protein arginine deiminases (PADs) are calcium-dependent enzymes that mediate the post-translational conversion of arginine into citrulline. Dysregulated PAD activity is associated with numerous autoimmune disorders and cancers. In breast cancer, PAD2 citrullinates histone H3R26 and activates the transcription of estrogen receptor target genes. However, PAD2 lacks a canonical nuclear localization sequence, and it is unclear how this enzyme is transported into the nucleus. Here, we show for the first time that PAD2 translocates into the nucleus in response to calcium signaling. Using BioID2, a proximity-dependent biotinylation method for identifying interacting proteins, we found that PAD2 preferentially associates with ANXA5 in the cytoplasm. Binding of calcium to PAD2 weakens this cytoplasmic interaction, which generates a pool of calcium-bound PAD2 that can interact with Ran. We hypothesize that this latter interaction promotes the translocation of PAD2 into the nucleus. These findings highlight a critical role for ANXA5 in regulating PAD2 and identify an unusual mechanism whereby proteins translocate between the cytosol and nucleus.
PAD2, ANXA5, Ran, BioID2, translocation, calcium dependency
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This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright © 2019 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.biochem.9b00225. Accepted manuscript posted after 12 months as allowed by publisher's Journal Publishing Agreement User’s Guide at https://pubs.acs.org/userimages/ContentEditor/1285231362937/jpa_user_guide.pdf.
DOI of Published Version
Biochemistry. 2019 Jul 9;58(27):3042-3056. doi: 10.1021/acs.biochem.9b00225. Epub 2019 Jun 27. Link to article on publisher's site
Zheng L, Nagar M, Maurais AJ, Slade DJ, Parelkar SS, Coonrod SA, Weerapana E, Thompson PR. (2019). Calcium Regulates the Nuclear Localization of Protein Arginine Deiminase 2. University of Massachusetts Medical School Publications.
https://doi.org/10.1021/acs.biochem.9b00225. Retrieved from https://escholarship.umassmed.edu/publications/19
Available for download on Friday, July 10, 2020