List Of Post-translational Modifications Research Articles

Catching Nucleosome by Its Decorated Tails Determines Its Functional States.

The fundamental packaging unit of chromatin, i.e., nucleosome, consists of ∼147 bp of DNA wrapped around a histone octamer composed of the core histones, H2A, H2B, H3, and H4, in two copies each. DNA packaged in nucleosomes must be accessible to various machineries, including replication, transcription, and DNA damage repair, implicating the dynamic nature of chromatin even in its compact state. As the tails protrude out of the nucleosome, they are easily accessible to various chromatin-modifying machineries and undergo post-translational modifications (PTMs), thus playing a critical role in epigenetic regulation. PTMs can regulate chromatin states via charge modulation on histones, affecting interaction with various chromatin-associated proteins (CAPs) and DNA. With technological advancement, the list of PTMs is ever-growing along with their writers, readers, and erasers, expanding the complexity of an already intricate epigenetic field. In this review, we discuss how some of the specific PTMs on flexible histone tails affect the nucleosomal structure and regulate the accessibility of chromatin from a mechanistic standpoint and provide structural insights into some newly identified PTM–reader interaction.

SnapShot: Histone Readers

Posttranslational modifications (PTMs) of histone proteins and methylation of DNA are major components of the epigenetic machinery that regulates the structure and dynamics of chromatin, gene transcription, DNA replication, DNA recombination, and DNA repair. The PTMs alter direct interactions between histones and DNA and serve as docking sites for epigenetic effectors. A number of PTMs have been identified in the flexible histone tails that protrude from the nucleosomal core and are readily accessible to histone acetyltransferases (HATs), histone deacetylases (HDACs), histone lysine methyltransferases (HKMTs), kinases, phosphatases, and other enzymes capable of depositing or removing PTMs. The list of PTMs is rapidly growing and includes acetylation, methylation, ubiquitination, and SUMOylation of lysine residues, methylation and citrullination of arginine residues, phosphorylation of serine and threonine residues, and ADP-ribosylation of glutamate and arginine residues. The histone PTMs are recognized by protein modules, referred to as epigenetic effectors, histone-binding domains, or simply “readers” of PTMs. Binding of the effectors recruits or stabilizes various transcription factors, chromatin remodeling complexes, and other components of the transcriptional network at chromatin. Many chromatin-associating proteins contain multiple copies of an effector or several different effectors, often specific for distinct PTMs. This provides a multivalent mechanism for targeting to a particular genomic site and ensures the proper biological outcome. Furthermore, the effectors are commonly found in macromolecules that either possess catalytic activities or act as scaffolding proteins that tether multisubunit enzymatic complexes to chromatin. These, in turn, further modify the epigenetic landscape by “erasing” PTMs, “writing” new epigenetic marks, or cleaving off the entire tail. This SnapShot shows the histone-binding effectors, their atomic-resolution structures, and the reported specificities for PTMs.

Oxygen Promotes Hydroxylation

Under normal oxygen conditions, hypoxia-inducible factor-1α (HIF-1α) is rapidly degraded through interaction with the E3 ubiquitin ligase von Hippel-Lindau tumor suppressor protein (VHL), which targets HIF-1α for degradation by the proteasome. Hypoxic conditions or treatment of cells with cobalt or desferrioxamine (a chelating agent) stabilizes HIF-1α and promotes its dissociation from VHL. Using a combination of in vitro assays (incubating purified protein with cytosolic extracts) and experiments with transfected cells, Yu et al. show that HIF-1α undergoes a posttranslational modification in the region of amino acids 549 to 575 that promotes VHL binding under normal oxygen conditions. Systematic mutation of the amino acids in this region showed that the regulated interaction with VHL was only disrupted if the sole proline (P 564 ) or the adjacent alanine (A 563 ) were mutated. Matrix-assisted laser desorption time of flight (MALDI-TOF) analysis (see the Protocol by Pandey et al. ) demonstrated that an HIF-1α fragment isolated from transfected cells showed a higher mass (consistent with a proline hydroxylation) under normal conditions than that isolated from cells exposed to cobalt. Final confirmation that proline hydroxylation promoted binding to VHL was provided by experiments with a peptide synthesized to contain 4-hydroxyl-L-proline, which bound VHL with or without incubation with cytoplasmic extracts, indicating that this modified peptide no longer required posttranslational modification to promote binding. Thus, reversible and regulated proline hydroxylation can be added to the list of posttranslational modifications controlling proteins involved in signal transduction. F. Yu, S. B. White, Q. Zhao, F. S. Lee, HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc. Natl. Acad. Sci. U.S.A. 98 , 9630-9635 (2001). [Abstract] [Full Text] A. Pandey, J. S. Andersen, M. Mann, Use of mass spectrometry to study signaling pathways. Science's STKE (2001), http://stke.sciencemag.org/cgi/content/full/OC_sigtrans;2000/37/pl1. [Full Text]