A substrate-specific inhibitor of protein translocation into the endoplasmic reticulum.
The segregation of secretory and membrane proteins to the mammalian endoplasmic reticulum is mediated by remarkably diverse signal sequences that have little or no homology with each other. Despite such sequence diversity, these signals are all recognized and interpreted by a highly conserved protein-conducting channel composed of the Sec61 complex. Signal recognition by Sec61 is essential for productive insertion of the nascent polypeptide into the translocation site, channel gating and initiation of transport. Although subtle differences in these steps can be detected between different substrates, it is not known whether they can be exploited to modulate protein translocation selectively. Here we describe cotransin, a small molecule that inhibits protein translocation into the endoplasmic reticulum. Cotransin acts in a signal-sequence-discriminatory manner to prevent the stable insertion of select nascent chains into the Sec61 translocation channel. Thus, the range of substrates accommodated by the channel can be specifically and reversibly modulated by a cell-permeable small molecule that alters the interaction between signal sequences and the Sec61 complex.
Garrison
Jennifer L
JL
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94107, USA.
Kunkel
Eric J
EJ
Hegde
Ramanujan S
RS
Taunton
Jack
J
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002474:Cell-Free System; D003432:Cross-Linking Reagents; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D021382:Protein Sorting Signals / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects; D000069816:SEC Translocation Channels; D013379:Substrate Specificity; D019010:Vascular Cell Adhesion Molecule-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D003432:Cross-Linking Reagents; C097977:HUN 7293; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D021382:Protein Sorting Signals; D000069816:SEC Translocation Channels; D019010:Vascular Cell Adhesion Molecule-1; C502316:cotransin; C502315:nor-cotransin