Abstract
Proteins targeted to the secretory pathway start their intracellular journey by being transported across biological membranes such as the endoplasmic reticulum (ER). A central component in this protein translocation process across the ER is the Sec61 translocon complex, which is only intracellularly expressed and does not have any enzymatic activity. In addition, Sec61 translocon complexes are difficult to purify and to reconstitute. Screening for small molecule inhibitors impairing its function has thus been notoriously difficult. However, such translocation inhibitors may not only be valuable tools for cell biology, but may also represent novel anticancer drugs, given that cancer cells heavily depend on efficient protein translocation into the ER to support their fast growth. In this review, different inhibitors of protein translocation will be discussed, and their specific mode of action will be compared. In addition, recently published screening strategies for small molecule inhibitors targeting the whole SRP-Sec61 targeting/translocation pathway will be summarized. Of note, slightly modified assays may be used in the future to screen for substances affecting SecYEG, the bacterial ortholog of the Sec61 complex, in order to identify novel antibiotic drugs.
Highlights
With the evolution of simple cellular structures to multi organelle compartmentalized cells, the transport of proteins across biological membranes has become an unavoidable challenge
Apratoxin A and Coibamide A are small molecules isolated from marine cyanobacteria that were originally investigated for their anticancer activity [121,122,123,124,125,126,127,128]
These structure–activity relationship (SAR) studies were all based on the biological effect of CADA analogs on the cellular expression of the huCD4 receptor, and structure optimization resulted in improved activity going from μM to the nM range [165]
Summary
With the evolution of simple cellular structures to multi organelle compartmentalized cells, the transport of proteins across biological membranes has become an unavoidable challenge. As SPs and TMDs are intrinsic targeting signals for the Sec dependent pathway for protein co- and post-translational translocation [8,14,23,24,25,26,27], C-terminally located targeting signals route the respective protein to a different translocation pathway. The specific C-terminal location of the targeting TMD, restrict TA proteins to the transmembrane recognition recognition complex complex subunit subunit of of the the 40. Single pass membrane proteins are translation is completed [22,28,29,30,31,32,33,34]. Single pass membrane proteins are oftenoften clasclassified based on their targeting signal topology after translocation
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