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Multisite protein modification and intramolecular signaling

Abstract

Post-translational modification is a major mechanism by which protein function is regulated in eukaryotes. Instead of single-site action, many proteins such as histones, p53, RNA polymerase II, tubulin, Cdc25C and tyrosine kinases are modified at multiple sites by modifications like phosphorylation, acetylation, methylation, ubiquitination, sumoylation and citrullination. Multisite modification on a protein constitutes a complex regulatory program that resembles a dynamic ‘molecular barcode’ and transduces molecular information to and from signaling pathways. This program imparts effects through ‘loss-of-function’ and ‘gain-of-function’ mechanisms. Among the latter, covalent modifications specifically recruit a diverse array of modules, including the SH2 domain, 14-3-3, WW domain, Polo box, BRCT repeat, bromodomain, chromodomain, Tudor domain and motifs binding to ubiquitin and other protein modifiers. Such recruitments are often modulated by modifications occurred at neighboring and distant sites. Multisite modification thus coordinates intermolecular and intramolecular signaling for the qualitative and quantitative control of protein function in vivo.

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Acknowledgements

This work was supported by funds from the Canadian Cancer Society through the National Cancer Institute of Canada and from the Canada Foundation for Innovation.

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Correspondence to Xiang-Jiao Yang.

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Yang, XJ. Multisite protein modification and intramolecular signaling. Oncogene 24, 1653–1662 (2005). https://doi.org/10.1038/sj.onc.1208173

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