Botch Is a γ-Glutamyl Cyclotransferase that Deglycinates and Antagonizes Notch

Zhikai Chi; Sean T. Byrne; Andrew Dolinko; Maged M. Harraz; Min Sik Kim; George Umanah; Jun Zhong; Rong Chen; Jianmin Zhang; Jinchong Xu; Li Chen; Akhilesh Pandey; Ted M. Dawson; Valina L. Dawson

doi:10.1016/j.celrep.2014.03.048

Botch Is a γ-Glutamyl Cyclotransferase that Deglycinates and Antagonizes Notch

Zhikai Chi, Sean T. Byrne, Andrew Dolinko, Maged M. Harraz, Min Sik Kim, George Umanah, Jun Zhong, Rong Chen, Jianmin Zhang, Jinchong Xu, Li Chen, Akhilesh Pandey, Ted M. Dawson, Valina L. Dawson

School of Medicine

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

Botch promotes embryonic neurogenesis by inhibiting the initial S1 furin-like cleavage step of Notch maturation. The biochemical process by which Botch inhibits Notch maturation is not known. Here, we show that Botch has γ-glutamyl cyclotransferase (GGCT) activity that deglycinates Notch, which prevents the S1 furin-like cleavage. Moreover, Notch is monoglycinated on the γ-glutamyl carbon of glutamate 1,669. The deglycinase activity of Botch is required for inhibition of Notch signaling both in vitro and in vivo. When the γ-glutamyl-glycine at position 1,669 of Notch is degylcinated, it is replaced by 5-oxy-proline. These results reveal that Botch regulates Notch signaling through deglycination and identify a posttranslational modification of Notch that plays an important role in neurogenesis.

Original language	English (US)
Pages (from-to)	681-688
Number of pages	8
Journal	Cell Reports
Volume	7
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2014.03.048
State	Published - 2014

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2014.03.048

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@article{ef51eea3438a46b1b59139d268ffd4bb,

title = "Botch Is a γ-Glutamyl Cyclotransferase that Deglycinates and Antagonizes Notch",

abstract = "Botch promotes embryonic neurogenesis by inhibiting the initial S1 furin-like cleavage step of Notch maturation. The biochemical process by which Botch inhibits Notch maturation is not known. Here, we show that Botch has γ-glutamyl cyclotransferase (GGCT) activity that deglycinates Notch, which prevents the S1 furin-like cleavage. Moreover, Notch is monoglycinated on the γ-glutamyl carbon of glutamate 1,669. The deglycinase activity of Botch is required for inhibition of Notch signaling both in vitro and in vivo. When the γ-glutamyl-glycine at position 1,669 of Notch is degylcinated, it is replaced by 5-oxy-proline. These results reveal that Botch regulates Notch signaling through deglycination and identify a posttranslational modification of Notch that plays an important role in neurogenesis.",

author = "Zhikai Chi and Byrne, {Sean T.} and Andrew Dolinko and Harraz, {Maged M.} and Kim, {Min Sik} and George Umanah and Jun Zhong and Rong Chen and Jianmin Zhang and Jinchong Xu and Li Chen and Akhilesh Pandey and Dawson, {Ted M.} and Dawson, {Valina L.}",

note = "Funding Information: This work was supported by a McKnight Foundation Neuroscience of Brain Disorders Award and USPHS NS40809, DA00266, and MSCRFII-0429 to V.L.D. and 1F31NS068010 to S.T.B. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. ",

year = "2014",

doi = "10.1016/j.celrep.2014.03.048",

language = "English (US)",

volume = "7",

pages = "681--688",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "3",

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TY - JOUR

T1 - Botch Is a γ-Glutamyl Cyclotransferase that Deglycinates and Antagonizes Notch

AU - Chi, Zhikai

AU - Byrne, Sean T.

AU - Dolinko, Andrew

AU - Harraz, Maged M.

AU - Kim, Min Sik

AU - Umanah, George

AU - Zhong, Jun

AU - Chen, Rong

AU - Zhang, Jianmin

AU - Xu, Jinchong

AU - Chen, Li

AU - Pandey, Akhilesh

AU - Dawson, Ted M.

AU - Dawson, Valina L.

N1 - Funding Information: This work was supported by a McKnight Foundation Neuroscience of Brain Disorders Award and USPHS NS40809, DA00266, and MSCRFII-0429 to V.L.D. and 1F31NS068010 to S.T.B. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases.

PY - 2014

Y1 - 2014

N2 - Botch promotes embryonic neurogenesis by inhibiting the initial S1 furin-like cleavage step of Notch maturation. The biochemical process by which Botch inhibits Notch maturation is not known. Here, we show that Botch has γ-glutamyl cyclotransferase (GGCT) activity that deglycinates Notch, which prevents the S1 furin-like cleavage. Moreover, Notch is monoglycinated on the γ-glutamyl carbon of glutamate 1,669. The deglycinase activity of Botch is required for inhibition of Notch signaling both in vitro and in vivo. When the γ-glutamyl-glycine at position 1,669 of Notch is degylcinated, it is replaced by 5-oxy-proline. These results reveal that Botch regulates Notch signaling through deglycination and identify a posttranslational modification of Notch that plays an important role in neurogenesis.

AB - Botch promotes embryonic neurogenesis by inhibiting the initial S1 furin-like cleavage step of Notch maturation. The biochemical process by which Botch inhibits Notch maturation is not known. Here, we show that Botch has γ-glutamyl cyclotransferase (GGCT) activity that deglycinates Notch, which prevents the S1 furin-like cleavage. Moreover, Notch is monoglycinated on the γ-glutamyl carbon of glutamate 1,669. The deglycinase activity of Botch is required for inhibition of Notch signaling both in vitro and in vivo. When the γ-glutamyl-glycine at position 1,669 of Notch is degylcinated, it is replaced by 5-oxy-proline. These results reveal that Botch regulates Notch signaling through deglycination and identify a posttranslational modification of Notch that plays an important role in neurogenesis.

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Botch Is a γ-Glutamyl Cyclotransferase that Deglycinates and Antagonizes Notch

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