O-GlcNAcylated peptides and proteins for structural and functional studies

Balana, Aaron T.; Moon, Stuart P.; Pratt, Matthew R.

doi:10.1016/j.sbi.2020.12.005

Cited by 6 publications

(6 citation statements)

References 71 publications

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“…Currently, the only way to study the site-specific consequences of O-GlcNAc on protein function is to generate homogeneously modified protein and subject it to direct biochemical testing. 30 For this purpose, our lab utilizes EPL 31,32 to prepare and study a variety of proteins. 33 This ligation technique traditionally involves the reaction between one peptide fragment bearing an N-terminal cysteine residue as the nucleophile and another bearing a C-terminal thioester as the leaving group.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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O-GlcNAcylation of High Mobility Group Box 1 (HMGB1) Alters Its DNA Binding and DNA Damage Processing Activities

et al. 2021

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Protein O-GlcNAcylation is an essential and dynamic regulator of myriad cellular processes, including DNA replication and repair. Proteomic studies have identified the multifunctional nuclear protein HMGB1 as O-GlcNAcylated, providing a potential link between this modification and DNA damage responses. Here, we verify the protein’s endogenous modification at S100 and S107 and found that the major modification site is S100, a residue that can potentially influence HMGB1-DNA interactions. Using synthetic protein chemistry, we generated site-specifically O-GlcNAc-modified HMGB1 at S100 and characterized biochemically the effect of the sugar modification on its DNA binding activity. We found that O-GlcNAc alters HMGB1 binding to linear, nucleosomal, supercoiled, cruciform, and interstrand cross-linked damaged DNA, generally resulting in enhanced oligomerization on these DNA structures. Using cell-free extracts, we also found that O-GlcNAc reduces the ability of HMGB1 to facilitate DNA repair, resulting in error-prone processing of damaged DNA. Our results expand our understanding of the molecular consequences of O-GlcNAc and how it affects protein–DNA interfaces. Importantly, our work may also support a link between upregulated O-GlcNAc levels and increased rates of mutations in certain cancer states.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

O-GlcNAcylation of High Mobility Group Box 1 (HMGB1) Alters Its DNA Binding and DNA Damage Processing Activities

et al. 2021

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“…Moreover, structures of human OGT − and OGA − have been elucidated recently, providing valuable insights into their catalytic and regulatory mechanisms. Besides these components, O-GlcNAcylated protein substrates have been gradually defined by using a series of chemical and biochemical tools/methods (including antibodies and especially mass spectrometry-based site-specific O-GlcNAc proteomics) developed along the years. − Significant improvements in technologies have triggered prevailing interest in O-GlcNAc studies (Figure A,B), as evidenced by the exponential increases in O-GlcNAc sites/proteins shown in several data sets recently. − Of note, although numerous proteins have been purposed to be potentially or putatively O-GlcNAcylated (mostly from high-throughput O-GlcNAc proteomics studies), , only a small portion of them were reported with O-GlcNAc peptides/sites (the definitive criteria for the confirmation of O-GlcNAc status) . So far, rigorous curation yielded over 5600 high-confidence proteins (matching with >11000 unambiguous O-GlcNAc sites and >10000 ambiguous sites) from dozens of species examined (Figure C,D).…”

Section: Introductionmentioning

confidence: 99%

Demystifying the O-GlcNAc Code: A Systems View

Hou

2022

Chem. Rev.

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Post-translational modification with O-linked β-N-acetylglucosamine (O-GlcNAc), a process referred to as O-GlcNAcylation, occurs on a vast variety of proteins. Mounting evidence in the past several decades has clearly demonstrated that O-GlcNAcylation is a unique and ubiquitous modification. Reminiscent of a code, protein O-GlcNAcylation functions as a crucial regulator of nearly all cellular processes studied. The primary aim of this review is to summarize the developments in our understanding of myriad protein substrates modified by O-GlcNAcylation from a systems perspective. Specifically, we provide a comprehensive survey of O-GlcNAcylation in multiple species studied, including eukaryotes (e.g., protists, fungi, plants, Caenorhabditis elegans, Drosophila melanogaster, murine, and human), prokaryotes, and some viruses. We evaluate features (e.g., structural properties and sequence motifs) of O-GlcNAc modification on proteins across species. Given that O-GlcNAcylation functions in a species-, tissue-/cell-, protein-, and site-specific manner, we discuss the functional roles of O-GlcNAcylation on human proteins. We focus particularly on several classes of relatively well-characterized human proteins (including transcription factors, protein kinases, protein phosphatases, and E3 ubiquitin-ligases), with representative O-GlcNAc site-specific functions presented. We hope the systems view of the great endeavor in the past 35 years will help demystify the O-GlcNAc code and lead to more fascinating studies in the years to come.

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“…N ‐glycosides including Nucleosides, glycoproteins and glycopeptides are essential components of DNA/RNA, enzymes and antibodies in living systems [65a,b] . N ‐Heterocyclic glycosides also exhibit important physiological properties such as antiviral, anticancer, antibacterial and antifungal activities or inhibition against several glycosidases [65c] .…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in the Synthesis of 5‐MemberedN‐Heterocycles via Rhodium Catalysed Cascade Reactions

et al. 2022

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Five membered N-heterocycles are significant targets in organic synthesis because of their ubiquitous existence in bioactive natural products and pharmaceuticals. Over the past decade a compelling attractiveness has grown to develop rhodium complex catalysed efficient and atom-economic chemistry to access structurally diverse N-heterocyclic frameworks. This present review enlightens notable progresses and advances in synthesis of 5-membered N-heterocycles via rhodium catalysed cascade reactions (annulations, CÀ H/CÀ C activation, cycloaddition, rearrangement, cyclization, metathesis) from 2018-2021.[a] D.

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O-GlcNAcylated peptides and proteins for structural and functional studies

Cited by 6 publications

References 71 publications

O-GlcNAcylation of High Mobility Group Box 1 (HMGB1) Alters Its DNA Binding and DNA Damage Processing Activities

O-GlcNAcylation of High Mobility Group Box 1 (HMGB1) Alters Its DNA Binding and DNA Damage Processing Activities

Demystifying the O-GlcNAc Code: A Systems View

Recent Advances in the Synthesis of 5‐MemberedN‐Heterocycles via Rhodium Catalysed Cascade Reactions

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