Multisite protein modi. cation and intramolecular signaling

Post-translational modi. cation 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 modi. cations like phosphorylation, acetylation, methylation, ubiquitination, sumoylation and citrullination. Multisite modi. cation 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 modi. cations 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 modi. cations occurred at neighboring and distant sites. Multisite modi. cation thus coordinates intermolecular and intramolecular signaling for the qualitative and quantitative control of protein function in vivo.