We study small molecule inhibitors of the Sec61 translocon, the major gateway of the secretory pathway of eukaryotic cells. These inhibitors block the translocation of all secreted and most transmemebrane proteins, which leads to their proteosomal degradation. Interestingly, some inhibitors block only a subset of Sec61 substrates. However, the determinants of this selectivity is still poorly understood.
A few years ago, Wenzell et al. developped a reporter library of signal peptide (the N-terminal segment of secreted and type I membrane proteins) that, combined with cell sorting and subsequence sequencing, enabled them to compared the activity of a pair of Sec61 inhibitors with different substrate selectivity on all signal peptides from the human proteome.
