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UNCONVENTIONAL ROLES OF HUMAN N-MYRISTOYLTRANSFERASES

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Abstract

N-myristoyltransferases (NMTs) are ubiquitous among eukaryotes and are widely known for adding a myristoyl, saturated 14-carbon chain, to the amino group of the N-terminal glycine on proteins. This modification in turn regulates essential protein properties such as membrane binding, stability, enzymatic activity, and interactions with other proteins. Decades of elegant studies have established the rules that govern this modification, such as the substrate sequence with the indispensable N-terminal glycine and co-translational mode of action. During my graduate work I discovered functions of NMT that do not conform to the known principles of this enzyme. I began my work with discovering that the small GTPase ADP-ribosylation factor 6 (ARF6) is myristoylated on lysine 3 in addition to its common to the ARF family N-terminal glycine myristoylation. Excitingly, this finding offered an explanation to the puzzling properties of ARF6 compared to ARF1-5 such as its retention at the membrane during the GTPase cycle. We became curious in finding the enzyme that adds this modification, however there was no reported mammalian lysine fatty-acyl transferases. Because N-terminal myristoylation occurs at the amino group, just like lysine myristoylation, my advisor Prof. Hening Lin suggested to test NMT. With the experimental help and suggestions of several amazing scientists, I demonstrated that it was indeed true. I then found that SIRT2 removes this modification, which closed the fascinating myristoylation-demyristoylation cycle essential for ARF6 activation. My following work focused on establishing the role of this cycle in colon cancer progression and on discovering other unconventional substrates of NMT such as Dynamin 2.

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157 pages

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2020-08

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Keywords

ARF6; ERK; Lysine myristoylation; N-myristoyltransferase; NMT; SIRT2

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Lin, Hening

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Committee Member

Cosgrove, Ben
Cerione, Richard A.
Pleiss, Jeffrey A.

Degree Discipline

Biochemistry, Molecular and Cell Biology

Degree Name

Ph. D., Biochemistry, Molecular and Cell Biology

Degree Level

Doctor of Philosophy

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Government Document

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dissertation or thesis

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