Alternative O-GlcNAcylation/O-Phosphorylation of Ser16 Induce Different Conformational Disturbances to the N Terminus of Murine Estrogen Receptor β

Chen, Yong-Xiang; Du, J.; Zhou, Lian-Xiu; Liu, Xiaohong; Zhao, Yufen; Nakanishi, Hiroshi; Li, Yanmei

doi:10.1016/j.chembiol.2006.06.017

Cited by 77 publications

(63 citation statements)

References 43 publications

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“…Although we were able to map O-GlcNAc sites only to previously identified phosphorylation sites, this observation does not preclude the possibility that there are Ser or Thr residues that are OGlcNAcylated only in vivo. NMR studies with O-GlcNAcylated and/or phosphorylated peptides from estrogen receptor β, from the heptad repeat from the C-terminal domain of RNA polymerase II, and from the microtubule-binding protein tau indicate that although phosphorylated peptides form an extended structure, O-GlcNAcylated peptides tend to form a β-turn (51)(52)(53). With these studies in mind, we suggest that O-GlcNAcylation could induce major changes in nucleosomal structure not only by regulating peptide backbone conformation but also because of its sheer size.…”

Section: Discussionmentioning

confidence: 99%

β- N -acetylglucosamine (O-GlcNAc) is part of the histone code

Sakabe

Wang

Hart

2010

Proc. Natl. Acad. Sci. U.S.A.

328

282

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Dynamic posttranslational modification of serine and threonine residues of nucleocytoplasmic proteins by β-N-acetylglucosamine (O-GlcNAc) is a regulator of cellular processes such as transcription, signaling, and protein-protein interactions. Like phosphorylation, O-GlcNAc cycles in response to a wide variety of stimuli. Although cycling of O-GlcNAc is catalyzed by only two highly conserved enzymes, O-GlcNAc transferase (OGT), which adds the sugar, and β-N-acetylglucosaminidase (O-GlcNAcase), which hydrolyzes it, the targeting of these enzymes is highly specific and is controlled by myriad interacting subunits. Here, we demonstrate by multiple specific immunological and enzymatic approaches that histones, the proteins that package DNA within the nucleus, are O-GlcNAcylated in vivo. Histones also are substrates for OGT in vitro. We identify O-GlcNAc sites on histones H2A, H2B, and H4 using mass spectrometry. Finally, we show that histone O-GlcNAcylation changes during mitosis and with heat shock. Taken together, these data show that O-GlcNAc cycles dynamically on histones and can be considered part of the histone code.epigenetics | histones

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Section: Discussionmentioning

confidence: 99%

β- N -acetylglucosamine (O-GlcNAc) is part of the histone code

Sakabe

Wang

Hart

2010

Proc. Natl. Acad. Sci. U.S.A.

328

282

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“…Further, they showed that common surfaces within GR affected by phosphorylation may be responsible for influencing the regulation of selective genes (7). Phosphorylationinduced conformational changes have also been proposed in the ID NTD of the estrogen receptor (8). ID activating regions of many TFs have been shown to function by recruiting the transcriptional apparatus to the promoter (24), and ID regions do indeed fold into a more ordered helical structure under physiological conditions (43).…”

Section: Discussionmentioning

confidence: 99%

Site-Specific Phosphorylation Induces Functionally Active Conformation in the Intrinsically Disordered N-Terminal Activation Function (AF1) Domain of the Glucocorticoid Receptor

Garza

Khan

Kumar

2010

Molecular and Cellular Biology

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Intrinsically disordered (ID) regions are disproportionately higher in cell signaling proteins and are predicted to have much larger frequency of phosphorylation sites than ordered regions, suggesting an important role in their regulatory capacity. In this study, we show that AF1, an ID activation domain of the glucocorticoid receptor (GR), adopts a functionally folded conformation due to its site-specific phosphorylation by p38 mitogen-activated protein kinase, which is involved in apoptotic and gene-inductive events initiated by the GR. Further, we show that site-specific phosphorylation-induced secondary and tertiary structure formation specifically facilitates AF1's interaction with critical coregulatory proteins and subsequently its transcriptional activity. These data demonstrate a mechanism through which ID activation domain of the steroid receptors and other similar transcription factors may adopt a functionally active conformation under physiological conditions.

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“…Most of the reported cases in the literature show competitive occupancy by O-GlcNAc or phosphate of the same or neighboring residues, and it is argued that the reciprocal exclusion results from either the large size of an O-GlcNAc residue (with an Stokes radius four to fivefold larger than a phosphate moiety) or by the negative charge of the phosphate group or by conformational changes induced by either modification (26). The observation of 23 doubly modified peptides with a median length of 24 residues suggest that both modifications cannot only occur simultaneously on distal sites of the same protein, but that also proximal residues can be occupied by O-GlcNAc and phosphate simultaneously.…”

Section: Fig 1 O-glcnac Protein Identification Strategymentioning

confidence: 99%

Discovery of O-GlcNAc-modified Proteins in Published Large-scale Proteome Data

Hahne

Gholami

Küster

2012

Molecular & Cellular Proteomics

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The attachment of N-acetylglucosamine to serine or threonine residues (O-GlcNAc) is a post-translational modification on nuclear and cytoplasmic proteins with emerging roles in numerous cellular processes, such as signal transduction, transcription, and translation. It is further presumed that O-GlcNAc can exhibit a site-specific, dynamic and possibly functional interplay with phosphorylation. OGlcNAc proteins are commonly identified by tandem mass spectrometry following some form of biochemical enrichment. In the present study, we assessed if, and to which extent, O-GlcNAc-modified proteins can be discovered from existing large-scale proteome data sets. To this end, we conceived a straightforward O-GlcNAc identification strategy based on our recently developed Oscore software that automatically analyzes tandem mass spectra for the presence and intensity of O-GlcNAc diagnostic fragment ions. Using the Oscore, we discovered hundreds of OGlcNAc peptides not initially identified in these studies, and most of which have not been described before. Merely re-searching this data extended the number of known OGlcNAc proteins by almost 100 suggesting that this modification exists even more widely than previously anticipated and the modification is often sufficiently abundant to be detected without enrichment. However, a comparison of O-GlcNAc and phospho-identifications from the very same data indicates that the O-GlcNAc modification is considerably less abundant than phosphorylation. The discovery of numerous doubly modified peptides (i.e. peptides with one or multiple O-GlcNAc or phosphate moieties), suggests that O-GlcNAc and phosphorylation are not necessarily mutually exclusive, but can occur simultaneously at adjacent sites. Molecular & Cellular

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Alternative O-GlcNAcylation/O-Phosphorylation of Ser16 Induce Different Conformational Disturbances to the N Terminus of Murine Estrogen Receptor β

Cited by 77 publications

References 43 publications

β- N -acetylglucosamine (O-GlcNAc) is part of the histone code

β- N -acetylglucosamine (O-GlcNAc) is part of the histone code

Site-Specific Phosphorylation Induces Functionally Active Conformation in the Intrinsically Disordered N-Terminal Activation Function (AF1) Domain of the Glucocorticoid Receptor

Discovery of O-GlcNAc-modified Proteins in Published Large-scale Proteome Data

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