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Defining a conformational consensus motif in cotransin-sensitive signal sequences: a proteomic and site-directed
Wolfgang Klein1, Carolin Westendorf1, Antje Schmidt1
1Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Str. 10, 13125, Berlin, Germany.
Plos One
|March 26, 2015
Summary
Cotransin inhibits protein biosynthesis by targeting the Sec61 channel. This study reveals cotransin sensitivity in most secreted proteins, but resistance in integral membrane proteins, identifying a novel motif in signal anchor sequences.
Area of Science:
- Molecular Biology
- Proteomics
- Cell Biology
Background:
- Cotransin inhibits protein biosynthesis via a signal sequence-discriminatory mechanism at the Sec61 protein-conducting channel.
- The selectivity of cotransin and the consensus motif for signal sequence sensitivity were previously unclear.
Purpose of the Study:
- To determine the selectivity of cotransin and identify the consensus motif responsible for cotransin sensitivity in signal sequences.
- To investigate the impact of cotransin on protein biosynthesis in human hepatocellular carcinoma cells.
Main Methods:
- Proteomic analysis of cotransin-treated human hepatocellular carcinoma cells.
- Stable isotope labeling by amino acids in cell culture (SILAC) combined with quantitative mass spectrometry.
- Utilized a saturating cotransin concentration (30 micromolar) to identify sensitive and resistant proteins.
Main Results:
- The biosynthesis of nearly all secreted proteins was found to be cotransin-sensitive.
- The majority of integral membrane proteins exhibited cotransin resistance.
- Identified a conformational consensus motif in signal anchor sequences mediating cotransin sensitivity, independent of signal sequence length or hydrophobicity.
Conclusions:
- Cotransin exhibits broad sensitivity among secreted proteins, with distinct resistance observed in integral membrane proteins.
- A novel conformational consensus motif in signal anchor sequences dictates cotransin sensitivity.
- This research clarifies cotransin's mechanism and identifies key features of sensitive signal sequences.
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