Discovery of functional motifs in h-regions of trypanosome signal sequences

Josh Duffy, Bhargavi Patham, Kojo Mensa-Wilmot

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

N-terminal signal peptides direct secretory proteins into the ER (endoplasmic reticulum) of eukaryotes or the periplasmic space of prokaryotes. A hydrophobic core (h-region) is important for signal sequence function; however, the mechanism of h-region action is not resolved. To gain new insight into signal sequences, bioinformatic analysis of h-regions from humans, Saccharomyces cerevisiae, Trypanosoma brucei and Escherichia coli was performed. Each species contains a unique set of peptide motifs (h-motifs) characterized by identity components (i.e. sequence of conserved amino acids) joined by spacers. Human h-motifs have four identity components, whereas those from the other species utilize three identity components. Example of h-motifs are human Hs3 {L-x(2)-[AGILPV]-L-x(0,2)-L}, S. cerevisiae Sc1 [L-x(0,2)-S-x(0,3)-A], T. brucei Tb2 {L-x(1,2)-L-[AILV]} and E. coli Ec1 [A-x(0,2)-L-x(0,3)-A]. The physiological relevance of h-motifs was tested with a T. brucei microsomal system for translocation of a VSG (variant surface glycoprotein)-117 signal peptide. Disruption of h-motifs by scrambling of sequences in h-regions produced defective signal peptides, although the hydrophobicity of the peptide was not altered. We conclude that: (i) h-regions harbour h-motifs, and are not random hydrophobic amino acids; (ii) h-regions from different species contain unique sets of h-motifs; and (iii) h-motifs contribute to the biological activity of ER signal peptides. h-Regions are 'scaffolds' in which functional h-motifs are embedded. A hypothetical model for h-motif interactions with a Sec61p protein translocon is presented.

Original languageEnglish (US)
Pages (from-to)135-145
Number of pages11
JournalBiochemical Journal
Volume426
Issue number2
DOIs
StatePublished - Mar 1 2010

Keywords

  • Endoplasmic reticulum
  • Hydrophobicity
  • Secretory protein
  • Signal sequence
  • Translocon
  • Trypanosome

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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