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.

Crosstalk between site-specific modifications on p53 and histone H3

“…Multisite modification of proteins is thought to constitute a complex regulatory program described as a dynamic 'molecular barcode' containing intermolecular and intramolecular signaling for the in vivo qualitative and quantitative control of protein function (Yang, 2005).…”

“…Core histone proteins undergo complex post-translational events resulting in a 'molecular barcode' similar to that described for the tumor suppressor p53 protein (Yang, 2005). Indeed, the 'histone code' hypothesis has been put forward identifying the interplay between various post-translational histone tail modifications that serve as markers for the recruitment of proteins which, when in complex with one another, regulate diverse chromatin functions, including DNA replication and gene expression (Jenuwein and Allis, 2001).…”

Class IIa histone deacetylases: regulating the regulators

“…Forty years later, it has become clear that lysine acetylation can target many cellular proteins in addition to histones. Similarly to phosphorylation, methylation or ubiquitination, lysine acetylation belongs to the panel of posttranslational modifications used by the cell to alter the specific properties of a given protein (Kouzarides, 2000;Yang, 2005;Yang and Gregoire, 2005). Lysine acetylation is a dynamic, reversible and tightly regulated protein modification.…”

Disordered epigenetic regulation in MLL-related leukemia

“…BRD4 binds to transcriptional start sites of genes during the M/G1 transition, influencing mitotic progression [55]. Notably, BRD4 is also a critical mediator of transcriptional elongation, functioning to recruit pTEFb [52,56]. The fact that BRD4 co-purifies with several components of the PAFc and SEC links BRD4 to MLL-rearranged leukemia.…”