Efficient farnesylation of an extended C-terminal C(x)3X sequence motif expands the scope of the prenylated proteome

Melanie J. Blanden, Kiall F. Suazo, Emily R. Hildebrandt, Daniel S. Hardgrove, Meet Patel, William P. Saunders, Mark D. Distefano, Walter K. Schmidt, James L. Hougland

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Protein prenylation is a post-translational modification that has been most commonly associated with enabling protein trafficking to and interaction with cellular membranes. In this process, an isoprenoid group is attached to a cysteine near the C terminus of a substrate protein by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type I or II (GGTase-I and GGTase-II). FTase and GGTase-I have long been proposed to specifically recognize a four-amino acid CAAX C-terminal sequence within their substrates. Surprisingly, genetic screening reveals that yeast FTase can modify sequences longer than the canonical CAAX sequence, specifically C(x)3X sequences with four amino acids downstream of the cysteine. Biochemical and cell-based studies using both peptide and protein substrates reveal that mammalian FTase orthologs can also prenylate C(x)3X sequences. As the search to identify physiologically relevant C(x)3X proteins begins, this new prenylation motif nearly doubles the number of proteins within the yeast and human proteomes that can be explored as potential FTase substrates. This work expands our understanding of prenylation's impact within the proteome, establishes the biologically relevant reactivity possible with this new motif, and opens new frontiers in determining the impact of non-canonically prenylated proteins on cell function.

Original languageEnglish (US)
Pages (from-to)2770-2785
Number of pages16
JournalJournal of Biological Chemistry
Issue number8
StatePublished - Feb 23 2018

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grants GM084152 (to M. D. D.) and GM117148 (to W. K. S.) and Department of Education Graduate Assistance in Areas of National Need (GAANN) Fellowship P200A090277 (to M. J. B.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the respon-sibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.


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