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

Cell Rep. 2014 May 8;7(3):681-8. doi: 10.1016/j.celrep.2014.03.048. Epub 2014 Apr 24.

Authors

Zhikai Chi¹, Sean T Byrne², Andrew Dolinko³, Maged M Harraz³, Min-Sik Kim⁴, George Umanah³, Jun Zhong⁴, Rong Chen³, Jianmin Zhang⁵, Jinchong Xu⁵, Li Chen³, Akhilesh Pandey⁶, Ted M Dawson⁷, Valina L Dawson⁸

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.
⁴ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.
⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
⁶ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA; Department of Biological Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA; Department of Pathology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, 401 North Broadway, Baltimore, MD 21205, USA.
⁷ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA. Electronic address: tdawson@jhmi.edu.
⁸ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA. Electronic address: vdawson@jhmi.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / metabolism
Embryo, Mammalian / enzymology
HEK293 Cells
Humans
Mice
Neurogenesis
Protein Structure, Tertiary
RNA Interference
RNA, Small Interfering / metabolism
Receptors, Notch / antagonists & inhibitors*
Receptors, Notch / metabolism
Signal Transduction
gamma-Glutamylcyclotransferase / antagonists & inhibitors
gamma-Glutamylcyclotransferase / chemistry
gamma-Glutamylcyclotransferase / metabolism*

Substances

GGCT protein, human
RNA, Small Interfering
Receptors, Notch
gamma-Glutamylcyclotransferase

Abstract

Publication types

MeSH terms

Substances

Grants and funding