The Non-catalytic Domains of O-GlcNAc Cycling Enzymes Present New Opportunities for Function-specific Control

Overview

Journal Curr Opin Chem Biol

Publisher Elsevier

Specialty Biochemistry

Date 2024 Jun 11

PMID 38861851

Authors

Chia-Wei Hu

Ke Wang

Jiaoyang Jiang

Affiliations

Soon will be listed here.

Abstract

O-GlcNAcylation is an essential protein glycosylation governed by two O-GlcNAc cycling enzymes: O-GlcNAc transferase (OGT) installs a single sugar moiety N-acetylglucosamine (GlcNAc) on protein serine and threonine residues, and O-GlcNAcase (OGA) removes them. Aberrant O-GlcNAcylation has been implicated in various diseases. However, the large repertoire of more than 1000 O-GlcNAcylated proteins and the elusive mechanisms of OGT/OGA in substrate recognition present significant challenges in targeting the dysregulated O-GlcNAcylation for therapeutic development. Recently, emerging evidence suggested that the non-catalytic domains play critical roles in regulating the functional specificity of OGT/OGA via modulating their protein interactions and substrate recognition. Here, we discuss recent studies on the structures, mechanisms, and related tools of the OGT/OGA non-catalytic domains, highlighting new opportunities for function-specific control.

Citing Articles

Evidence for Functional Regulation of the KLHL3/WNK Pathway by O-GlcNAcylation.

Hu J, Huynh D, Dunn D, Wu J, Manriquez-Rodriguez C, Zhang Q bioRxiv. 2025; .

PMID: 40060460 PMC: 11888436. DOI: 10.1101/2025.02.27.640596.

References

Stephen H, Praissman J, Wells L . Generation of an Interactome for the Tetratricopeptide Repeat Domain of O-GlcNAc Transferase Indicates a Role for the Enzyme in Intellectual Disability. J Proteome Res. 2020; 20(2):1229-1242. PMC: 8577549. DOI: 10.1021/acs.jproteome.0c00604. View

Gao Y, Wells L, Comer F, Parker G, Hart G . Dynamic O-glycosylation of nuclear and cytosolic proteins: cloning and characterization of a neutral, cytosolic beta-N-acetylglucosaminidase from human brain. J Biol Chem. 2001; 276(13):9838-45. DOI: 10.1074/jbc.M010420200. View

Wulff-Fuentes E, Berendt R, Massman L, Danner L, Malard F, Vora J . The human O-GlcNAcome database and meta-analysis. Sci Data. 2021; 8(1):25. PMC: 7820439. DOI: 10.1038/s41597-021-00810-4. View

Roth C, Chan S, Offen W, Hemsworth G, Willems L, King D . Structural and functional insight into human O-GlcNAcase. Nat Chem Biol. 2017; 13(6):610-612. PMC: 5438047. DOI: 10.1038/nchembio.2358. View

Oldfield C, Dunker A . Intrinsically disordered proteins and intrinsically disordered protein regions. Annu Rev Biochem. 2014; 83:553-84. DOI: 10.1146/annurev-biochem-072711-164947. View

He Q, Yang M, Huang J, Wu W, Tang K, Zhang Y . Hypoxia-triggered O-GlcNAcylation in the brain drives the glutamate-glutamine cycle and reduces sensitivity to sevoflurane in mice. Br J Anaesth. 2022; 129(5):703-715. DOI: 10.1016/j.bja.2022.06.041. View

Jinek M, Rehwinkel J, Lazarus B, Izaurralde E, Hanover J, Conti E . The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin alpha. Nat Struct Mol Biol. 2004; 11(10):1001-7. DOI: 10.1038/nsmb833. View

Bond M, Hanover J . A little sugar goes a long way: the cell biology of O-GlcNAc. J Cell Biol. 2015; 208(7):869-80. PMC: 4384737. DOI: 10.1083/jcb.201501101. View

Kositzke A, Fan D, Wang A, Li H, Worth M, Jiang J . Elucidating the protein substrate recognition of O-GlcNAc transferase (OGT) toward O-GlcNAcase (OGA) using a GlcNAc electrophilic probe. Int J Biol Macromol. 2020; 169:51-59. PMC: 7856287. DOI: 10.1016/j.ijbiomac.2020.12.078. View

10.

Ge Y, Ramirez D, Yang B, DSouza A, Aonbangkhen C, Wong S . Target protein deglycosylation in living cells by a nanobody-fused split O-GlcNAcase. Nat Chem Biol. 2021; 17(5):593-600. PMC: 8085020. DOI: 10.1038/s41589-021-00757-y. View

11.

Comtesse N, Maldener E, Meese E . Identification of a nuclear variant of MGEA5, a cytoplasmic hyaluronidase and a beta-N-acetylglucosaminidase. Biochem Biophys Res Commun. 2001; 283(3):634-40. DOI: 10.1006/bbrc.2001.4815. View

12.

Lazarus M, Jiang J, Kapuria V, Bhuiyan T, Janetzko J, Zandberg W . HCF-1 is cleaved in the active site of O-GlcNAc transferase. Science. 2013; 342(6163):1235-9. PMC: 3930058. DOI: 10.1126/science.1243990. View

13.

Davey N, Simonetti L, Ivarsson Y . ProP-PD for proteome-wide motif-mediated interaction discovery. Trends Biochem Sci. 2022; 47(6):547-548. DOI: 10.1016/j.tibs.2022.01.005. View

14.

Elsen N, Patel S, Ford R, Hall D, Hess F, Kandula H . Insights into activity and inhibition from the crystal structure of human O-GlcNAcase. Nat Chem Biol. 2017; 13(6):613-615. DOI: 10.1038/nchembio.2357. View

15.

Li B, Li H, Hu C, Jiang J . Structural insights into the substrate binding adaptability and specificity of human O-GlcNAcase. Nat Commun. 2017; 8(1):666. PMC: 5610315. DOI: 10.1038/s41467-017-00865-1. View

16.

Alteen M, Meek R, Kolappan S, Busmann J, Cao J, OGara Z . Phage display uncovers a sequence motif that drives polypeptide binding to a conserved regulatory exosite of O-GlcNAc transferase. Proc Natl Acad Sci U S A. 2023; 120(42):e2303690120. PMC: 10589721. DOI: 10.1073/pnas.2303690120. View

17.

Levine Z, Walker S . The Biochemistry of O-GlcNAc Transferase: Which Functions Make It Essential in Mammalian Cells?. Annu Rev Biochem. 2016; 85:631-57. DOI: 10.1146/annurev-biochem-060713-035344. View

18.

Lockridge A, Hanover J . A nexus of lipid and Glcnac metabolism in physiology and disease. Front Endocrinol (Lausanne). 2022; 13:943576. PMC: 9468787. DOI: 10.3389/fendo.2022.943576. View

19.

Perez-Riba A, Itzhaki L . The tetratricopeptide-repeat motif is a versatile platform that enables diverse modes of molecular recognition. Curr Opin Struct Biol. 2019; 54:43-49. DOI: 10.1016/j.sbi.2018.12.004. View

20.

Cui Y, Xie R, Zhang X, Liu Y, Hu Y, Li Y . OGA is associated with deglycosylation of NONO and the KU complex during DNA damage repair. Cell Death Dis. 2021; 12(7):622. PMC: 8209095. DOI: 10.1038/s41419-021-03910-6. View