Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins

Research output: Contribution to journal › Journal article › Research › peer-review

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Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins. / Larsen, Ida Signe Bohse; Narimatsu, Yoshiki; Joshi, Hiren Jitendra; Siukstaite, Lina; Harrison, Oliver J; Brasch, Julia; Goodman, Kerry M; Hansen, Lars; Shapiro, Lawrence; Honig, Barry; Vakhrushev, Sergey Y; Clausen, Henrik; Halim, Adnan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 42, 2017, p. 11163-11168.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Larsen, ISB, Narimatsu, Y, Joshi, HJ, Siukstaite, L, Harrison, OJ, Brasch, J, Goodman, KM, Hansen, L, Shapiro, L, Honig, B, Vakhrushev, SY, Clausen, H & Halim, A 2017, 'Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 42, pp. 11163-11168. https://doi.org/10.1073/pnas.1708319114

APA

Larsen, I. S. B., Narimatsu, Y., Joshi, H. J., Siukstaite, L., Harrison, O. J., Brasch, J., Goodman, K. M., Hansen, L., Shapiro, L., Honig, B., Vakhrushev, S. Y., Clausen, H., & Halim, A. (2017). Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins. Proceedings of the National Academy of Sciences of the United States of America, 114(42), 11163-11168. https://doi.org/10.1073/pnas.1708319114

Vancouver

Larsen ISB, Narimatsu Y, Joshi HJ, Siukstaite L, Harrison OJ, Brasch J et al. Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(42):11163-11168. https://doi.org/10.1073/pnas.1708319114

Author

Larsen, Ida Signe Bohse ; Narimatsu, Yoshiki ; Joshi, Hiren Jitendra ; Siukstaite, Lina ; Harrison, Oliver J ; Brasch, Julia ; Goodman, Kerry M ; Hansen, Lars ; Shapiro, Lawrence ; Honig, Barry ; Vakhrushev, Sergey Y ; Clausen, Henrik ; Halim, Adnan. / Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 42. pp. 11163-11168.

Bibtex

@article{9b9ffdbc5e0942559429b8ab0db9a4f5,
title = "Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins",
abstract = "The cadherin (cdh) superfamily of adhesion molecules carry O-linked mannose (O-Man) glycans at highly conserved sites localized to specific β-strands of their extracellular cdh (EC) domains. These O-Man glycans do not appear to be elongated like O-Man glycans found on α-dystroglycan (α-DG), and we recently demonstrated that initiation of cdh/protocadherin (pcdh) O-Man glycosylation is not dependent on the evolutionary conserved POMT1/POMT2 enzymes that initiate O-Man glycosylation on α-DG. Here, we used a CRISPR/Cas9 genetic dissection strategy combined with sensitive and quantitative O-Man glycoproteomics to identify a homologous family of four putative protein O-mannosyltransferases encoded by the TMTC1-4 genes, which were found to be imperative for cdh and pcdh O-Man glycosylation. KO of all four TMTC genes in HEK293 cells resulted in specific loss of cdh and pcdh O-Man glycosylation, whereas combined KO of TMTC1 and TMTC3 resulted in selective loss of O-Man glycans on specific β-strands of EC domains, suggesting that each isoenzyme serves a different function. In addition, O-Man glycosylation of IPT/TIG domains of plexins and hepatocyte growth factor receptor was not affected in TMTC KO cells, suggesting the existence of yet another O-Man glycosylation machinery. Our study demonstrates that regulation of O-mannosylation in higher eukaryotes is more complex than envisioned, and the discovery of the functions of TMTCs provide insight into cobblestone lissencephaly caused by deficiency in TMTC3.",
keywords = "Journal Article",
author = "Larsen, {Ida Signe Bohse} and Yoshiki Narimatsu and Joshi, {Hiren Jitendra} and Lina Siukstaite and Harrison, {Oliver J} and Julia Brasch and Goodman, {Kerry M} and Lars Hansen and Lawrence Shapiro and Barry Honig and Vakhrushev, {Sergey Y} and Henrik Clausen and Adnan Halim",
year = "2017",
doi = "10.1073/pnas.1708319114",
language = "English",
volume = "114",
pages = "11163--11168",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "42",

}

RIS

TY - JOUR

T1 - Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins

AU - Larsen, Ida Signe Bohse

AU - Narimatsu, Yoshiki

AU - Joshi, Hiren Jitendra

AU - Siukstaite, Lina

AU - Harrison, Oliver J

AU - Brasch, Julia

AU - Goodman, Kerry M

AU - Hansen, Lars

AU - Shapiro, Lawrence

AU - Honig, Barry

AU - Vakhrushev, Sergey Y

AU - Clausen, Henrik

AU - Halim, Adnan

PY - 2017

Y1 - 2017

N2 - The cadherin (cdh) superfamily of adhesion molecules carry O-linked mannose (O-Man) glycans at highly conserved sites localized to specific β-strands of their extracellular cdh (EC) domains. These O-Man glycans do not appear to be elongated like O-Man glycans found on α-dystroglycan (α-DG), and we recently demonstrated that initiation of cdh/protocadherin (pcdh) O-Man glycosylation is not dependent on the evolutionary conserved POMT1/POMT2 enzymes that initiate O-Man glycosylation on α-DG. Here, we used a CRISPR/Cas9 genetic dissection strategy combined with sensitive and quantitative O-Man glycoproteomics to identify a homologous family of four putative protein O-mannosyltransferases encoded by the TMTC1-4 genes, which were found to be imperative for cdh and pcdh O-Man glycosylation. KO of all four TMTC genes in HEK293 cells resulted in specific loss of cdh and pcdh O-Man glycosylation, whereas combined KO of TMTC1 and TMTC3 resulted in selective loss of O-Man glycans on specific β-strands of EC domains, suggesting that each isoenzyme serves a different function. In addition, O-Man glycosylation of IPT/TIG domains of plexins and hepatocyte growth factor receptor was not affected in TMTC KO cells, suggesting the existence of yet another O-Man glycosylation machinery. Our study demonstrates that regulation of O-mannosylation in higher eukaryotes is more complex than envisioned, and the discovery of the functions of TMTCs provide insight into cobblestone lissencephaly caused by deficiency in TMTC3.

AB - The cadherin (cdh) superfamily of adhesion molecules carry O-linked mannose (O-Man) glycans at highly conserved sites localized to specific β-strands of their extracellular cdh (EC) domains. These O-Man glycans do not appear to be elongated like O-Man glycans found on α-dystroglycan (α-DG), and we recently demonstrated that initiation of cdh/protocadherin (pcdh) O-Man glycosylation is not dependent on the evolutionary conserved POMT1/POMT2 enzymes that initiate O-Man glycosylation on α-DG. Here, we used a CRISPR/Cas9 genetic dissection strategy combined with sensitive and quantitative O-Man glycoproteomics to identify a homologous family of four putative protein O-mannosyltransferases encoded by the TMTC1-4 genes, which were found to be imperative for cdh and pcdh O-Man glycosylation. KO of all four TMTC genes in HEK293 cells resulted in specific loss of cdh and pcdh O-Man glycosylation, whereas combined KO of TMTC1 and TMTC3 resulted in selective loss of O-Man glycans on specific β-strands of EC domains, suggesting that each isoenzyme serves a different function. In addition, O-Man glycosylation of IPT/TIG domains of plexins and hepatocyte growth factor receptor was not affected in TMTC KO cells, suggesting the existence of yet another O-Man glycosylation machinery. Our study demonstrates that regulation of O-mannosylation in higher eukaryotes is more complex than envisioned, and the discovery of the functions of TMTCs provide insight into cobblestone lissencephaly caused by deficiency in TMTC3.

KW - Journal Article

U2 - 10.1073/pnas.1708319114

DO - 10.1073/pnas.1708319114

M3 - Journal article

C2 - 28973932

VL - 114

SP - 11163

EP - 11168

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 42

ER -

ID: 185902059