Larsen, I.S.B., Povolo, L. orcid.org/0000-0001-7927-823X, Zhou, L. et al. (17 more authors) (2023) The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase. Proceedings of the National Academy of Sciences, 120 (21). e2302584120. ISSN 0027-8424
Abstract
Mutations in the TMEM260 gene cause structural heart defects and renal anomalies syndrome, but the function of the encoded protein remains unknown. We previously reported wide occurrence of O-mannose glycans on extracellular immunoglobulin, plexin, transcription factor (IPT) domains found in the hepatocyte growth factor receptor (cMET), macrophage-stimulating protein receptor (RON), and plexin receptors, and further demonstrated that two known protein O-mannosylation systems orchestrated by the POMT1/2 and transmembrane and tetratricopeptide repeat-containing proteins 1-4 gene families were not required for glycosylation of these IPT domains. Here, we report that the TMEM260 gene encodes an ER-located protein O-mannosyltransferase that selectively glycosylates IPT domains. We demonstrate that disease-causing TMEM260 mutations impair O-mannosylation of IPT domains and that TMEM260 knockout in cells results in receptor matura-tion defects and abnormal growth of 3D cell models. Thus, our study identifies the third protein-specific O-mannosylation pathway in mammals and demonstrates that O-mannosylation of IPT domains serves critical functions during epithelial morpho-genesis. Our findings add a new glycosylation pathway and gene to a growing group of congenital disorders of glycosylation.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This is an author produced version of a conference paper published in the Proceedings of the National Academy of Sciences. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | glycosylation; congenital disorders of glycosylation; O-mannosylation; glycoproteomics; plexin |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Medical Research (LIMR) > Division of Molecular Medicine |
Depositing User: | Symplectic Publications |
Date Deposited: | 11 Oct 2023 12:29 |
Last Modified: | 15 Nov 2023 01:13 |
Published Version: | https://www.pnas.org/doi/10.1073/pnas.2302584120 |
Status: | Published |
Publisher: | Proceedings of the National Academy of Sciences |
Identification Number: | 10.1073/pnas.2302584120 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:203373 |