Structural insights into the substrate binding adaptability and specificity of human O-GlcNAcase

Li, Baobin; Li, Hao; Hu, Chia‐Wei; Jiang, Jiaoyang

doi:10.1038/s41467-017-00865-1

Cited by 47 publications

(56 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to OGT, the single OGA gene can encode two isoforms, namely a short isoform which appears inactive and the full length isoform [65]. Interestingly, OGA seems to form dimers and the intersubunit interactions differ between catalytically active and compromised OGA variants, indicating that the dimerization of OGA could also influence the binding of substrates and affect OGA activity [68][69][70][71]. In addition, full-length OGA contains a caspase-3 cleavage site, although cleavage at this site does not reduce the enzymatic activity of OGA [67,68].…”

Section: Regulation Of O-glcnacylationmentioning

confidence: 99%

“…In addition, full-length OGA contains a caspase-3 cleavage site, although cleavage at this site does not reduce the enzymatic activity of OGA [67,68]. Interestingly, OGA seems to form dimers and the intersubunit interactions differ between catalytically active and compromised OGA variants, indicating that the dimerization of OGA could also influence the binding of substrates and affect OGA activity [68][69][70][71].…”

Section: Regulation Of O-glcnacylationmentioning

confidence: 99%

See 1 more Smart Citation

Crosstalk between phosphorylation and O‐GlcNAcylation: friend or foe

2018

View full text Add to dashboard Cite

A wide variety of protein post-translational modifications (PTMs) decorate cellular proteins, regulating their structure, interactions and ultimately their function. The density of co-occurring PTMs on proteins can be very high, where multiple PTMs can positively or negatively influence each other's actions, termed PTM crosstalk. In this review, we highlight recent progress in the area of PTM crosstalk, whereby we focus on crosstalk between protein phosphorylation and O-GlcNAcylation. These two PTMs largely target identical (i.e., Ser and Thr) amino acids in proteins. Phosphorylation/O-GlcNAcylation crosstalk comes in many flavors, for instance by competition for the same site/residue (reciprocal crosstalk), as well as by modifications influencing each other in proximity or even distal on the protein sequence. PTM crosstalk is observed on the writers of these modifications (i.e., kinases and O-GlcNAc transferase), on the erasers (i.e., phosphatases and O-GlcNAcase), and on the readers and the substrates. We describe examples of all these different flavors of crosstalk, and additionally the methods that are emerging to better investigate in particular phosphorylation/O-GlcNAcylation crosstalk.

show abstract

Section: Regulation Of O-glcnacylationmentioning

confidence: 99%

Section: Regulation Of O-glcnacylationmentioning

confidence: 99%

Crosstalk between phosphorylation and O‐GlcNAcylation: friend or foe

2018

View full text Add to dashboard Cite

show abstract

“…Whereas less is known about how OGA is targeted to it substrates, several recent studies have defined its detailed structure. These studies have also elucidated the molecular mechanisms of the enzyme, and they have led to the development of highly specific and potent OGA inhibitors that work in living cells (43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53).…”

mentioning

confidence: 99%

Nutrient regulation of signaling and transcription

Hart

2019

Journal of Biological Chemistry

289

225

View full text Add to dashboard Cite

O‐GlcNAc cycles on and off thousands of nucleocytoplasmic proteins and has extensive crosstalk with protein phosphorylation. O‐GlcNAc cycles on nearly all proteins involved in transcription, where it regulates gene expression in response to nutrients. O‐GlcNAc also regulates the cycling of the TATA‐binding (TBP) protein on and off DNA during the transcription cycle. Targeted, inducible, deletion of the O‐GlcNAc Transferase (OGT) in aCAMKII positive (excitatory) neurons of adult mice results in a morbidly obese mouse with a satiety defect. Thus, O‐GlcNAcylation not only serves as a nutrient sensor in all cells, but also is directly involved in appetite regulation. O‐GlcNAcylation also plays an important role in the trafficking of the AMPA receptors in neurons and in the development of functional synaptic spines. Recent studies have shown that more than one‐half of all human protein kinases are modified by O‐GlcNAc and all kinases that have been tested are indeed regulated in some way by the sugar. Abnormal O‐GlcNAcylation of CAMKII contributes directly to diabetic cardiomyopathy and to arrhythmias associated with diabetes. Prolonged elevation of O‐GlcNAc, as occurs in diabetes, contributes directly to diabetic complications and is a major mechanism of glucose toxicity. Drugs that elevate O‐GlcNAcylation in the brain, which, in‐turn, prevents hyperphosphorylation, appear to be of benefit for the treatment of Alzheimer's disease in animal models. To date, all cancers have elevated O‐GlcNAc cycling, which may play a key role in the regulation of metabolism in cancer cells. Support or Funding Information Supported by NIH P01HL107153, R01GM116891, R01DK61671, and N01‐HV‐00240. Dr. Hart receives a share of royalty received by the university on sales of the CTD 110.6 antibody, which are managed by JHU. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

show abstract

“…Intriguingly, a potential substrate‐binding cleft created by the dimerized OGA protein was discovered. In support of this, the structures of OGA in complex with each of five distinct glycopeptides demonstrate that all the peptide substrates are bound in the substrate‐binding cleft . The interactions of GlcNAc in the OGA catalytic pocket are highly conserved, whereas peptides are bound in a bidirectional yet generally similar V‐shaped conformation.…”

Section: Introductionmentioning

confidence: 76%

Chemical and Biochemical Strategies To Explore the Substrate Recognition of O‐GlcNAc‐Cycling Enzymes

Worth

et al. 2018

ChemBioChem

Self Cite

View full text Add to dashboard Cite

The O-linked N-acetylglucosamine (O-GlcNAc) modification is an essential component in cell regulation. A single pair of human enzymes conducts this modification dynamically on a broad variety of proteins: O-GlcNAc transferase (OGT) adds the GlcNAc residue and O-GlcNAcase (OGA) hydrolyzes it. This modification is dysregulated in many diseases, but its exact effect on particular substrates remains unclear. In addition, no apparent sequence motif has been found in the modified proteins, and the factors controlling the substrate specificity of OGT and OGA are largely unknown. In this minireview, we will discuss recent developments in chemical and biochemical methods toward addressing the challenge of OGT and OGA substrate recognition. We hope that the new concepts and knowledge from these studies will promote research in this area to advance understanding of O-GlcNAc regulation in health and disease.

show abstract

Structural insights into the substrate binding adaptability and specificity of human O-GlcNAcase

Cited by 47 publications

References 27 publications

Crosstalk between phosphorylation and O‐GlcNAcylation: friend or foe

Crosstalk between phosphorylation and O‐GlcNAcylation: friend or foe

Nutrient regulation of signaling and transcription

Chemical and Biochemical Strategies To Explore the Substrate Recognition of O‐GlcNAc‐Cycling Enzymes

Contact Info

Product

Resources

About