Sequence requirement for peptide recognition by rat brain p21(ras) protein farnesyltransferase

Yuval Reiss, Sarah J. Stradley, Lila M. Gierasch, Michael S. Brown, Joseph L. Goldstein

Research output: Contribution to journalArticlepeer-review

306 Scopus citations

Abstract

We tested 42 tetrapeptides for their ability to bind to the rat brain p21(ras) protein farnesyltransferase as estimated by their ability to compete with p21(Ha-ras) in a farnesyl-transfer assay. Peptides with the highest affinity had the structure Cys-A1-A2-X, where positions A1 and A2 are occupied by aliphatic amino acids and position X is occupied by a COOH-terminal methionine, serine, or phenylalanine. Charged residues reduced affinity slightly at the A1 position and much more drastically at the A2 and X positions. Effective inhibitors included tetrapeptides corresponding to the COOH termini of all animal cell proteins known to be farnesylated. In contrast, the tetrapeptide Cys-Ala-Ile-Leu (CAIL), which corresponds to the COOH termini of several neural guanine nucleotide binding (G) protein γ subunits, did not compete in the farnesyl-transfer assay. Inasmuch as several of these proteins are geranylgeranylated, the data suggest that the two isoprenes (farnesyl and geranylgeranyl) are transferred by different enzymes. A biotinylated heptapeptide corresponding to the COOH terminus of p21(Ki-rasB) was farnesylated, suggesting that at least some of the peptides serve as substrates for the transferase. The data are consistent with a model in which a hydrophobic pocket in the protein farnesyltransferase recognizes tetrapeptides through interactions with the cysteine and the last two amino acids.

Original languageEnglish (US)
Pages (from-to)732-736
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume88
Issue number3
DOIs
StatePublished - 1991

Keywords

  • covalent modification
  • enzyme inhibition
  • mevalonate
  • prenylation
  • tetrapeptides

ASJC Scopus subject areas

  • General

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