Towards the systematic mapping and engineering of the protein prenylation machinery in Saccharomyces cerevisiae

PloS One
Viktor SteinKirill Alexandrov

Abstract

Protein prenylation is a widespread and highly conserved eukaryotic post-translational modification that endows proteins with the ability to reversibly attach to intracellular membranes. The dynamic interaction of prenylated proteins with intracellular membranes is essential for their signalling functions and is frequently deregulated in disease processes such as cancer. As a result, protein prenylation has been pharmacologically targeted by numerous drug discovery programs, albeit with limited success. To a large extent, this can be attributed to an insufficient understanding of the interplay of different protein prenyltransferases and the combinatorial diversity of the prenylatable sequence space. Here, we report a high-throughput, growth-based genetic selection assay in Saccharomyces cerevisiae based on the Ras Recruitment System which, for the first time, has allowed us to create a comprehensive map of prenylatable protein sequences in S. cerevisiae. We demonstrate that potential prenylatable space is sparsely (6.2%) occupied leaving room for creation of synthetic orthogonal prenylatable sequences. To experimentally demonstrate that, we used the developed platform to engineer mutant farnesyltransferases that efficiently pre...Continue Reading

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Citations

Jan 25, 2016·Bioorganic & Medicinal Chemistry Letters·Benjamin C JenningsCarol A Fierke
Feb 10, 2018·Critical Reviews in Biochemistry and Molecular Biology·Shahienaz E HamptonWalter K Schmidt

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Methods Mentioned

BETA
GTPases
PCR
Chip
Infrared Imaging
Assay
myristoylation
GTPase

Software Mentioned

Ion
Sigma OligoEvaluator
USER Enzyme

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