Efficient farnesylation of an extended C-terminal C(x) 3 X 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 journalArticle

9 Citations (Scopus)

Abstract

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) 3 X 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) 3 X sequences. As the search to identify physiologically relevant C(x) 3 X 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
Volume293
Issue number8
DOIs
StatePublished - Jan 1 2018

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Farnesyltranstransferase
Prenylation
Proteome
Cysteine
Proteins
Protein Prenylation
Amino Acids
Substrates
Fungal Proteins
Terpenes
Genetic Testing
Yeast
Protein Transport
Post Translational Protein Processing
Yeasts
Peptides
Membranes
geranylgeranyltransferase type-I
Screening
Rab geranylgeranyl transferase beta-subunit

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

Cite this

Blanden, M. J., Suazo, K. F., Hildebrandt, E. R., Hardgrove, D. S., Patel, M., Saunders, W. P., ... Hougland, J. L. (2018). Efficient farnesylation of an extended C-terminal C(x) 3 X sequence motif expands the scope of the prenylated proteome Journal of Biological Chemistry, 293(8), 2770-2785. https://doi.org/10.1074/jbc.M117.805770

Efficient farnesylation of an extended C-terminal C(x) 3 X sequence motif expands the scope of the prenylated proteome . / Blanden, Melanie J.; Suazo, Kiall F.; Hildebrandt, Emily R.; Hardgrove, Daniel S.; Patel, Meet; Saunders, William P.; Distefano, Mark D; Schmidt, Walter K.; Hougland, James L.

In: Journal of Biological Chemistry, Vol. 293, No. 8, 01.01.2018, p. 2770-2785.

Research output: Contribution to journalArticle

Blanden, MJ, Suazo, KF, Hildebrandt, ER, Hardgrove, DS, Patel, M, Saunders, WP, Distefano, MD, Schmidt, WK & Hougland, JL 2018, ' Efficient farnesylation of an extended C-terminal C(x) 3 X sequence motif expands the scope of the prenylated proteome ', Journal of Biological Chemistry, vol. 293, no. 8, pp. 2770-2785. https://doi.org/10.1074/jbc.M117.805770
Blanden, Melanie J. ; Suazo, Kiall F. ; Hildebrandt, Emily R. ; Hardgrove, Daniel S. ; Patel, Meet ; Saunders, William P. ; Distefano, Mark D ; Schmidt, Walter K. ; Hougland, James L. / Efficient farnesylation of an extended C-terminal C(x) 3 X sequence motif expands the scope of the prenylated proteome In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 8. pp. 2770-2785.
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