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Selective inhibition of protein secretion by abrogating receptor-coat interactions during ER export.

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Gomez-Navarro, Natalia  ORCID logo
Maldutyte, Julija 
Poljak, Kristina 
Orme, Jonathon 


Protein secretion is an essential process that drives cell growth, movement, and communication. Protein traffic within the secretory pathway occurs via transport intermediates that bud from one compartment and fuse with a downstream compartment to deliver their contents. Here, we explore the possibility that protein secretion can be selectively inhibited by perturbing protein-protein interactions that drive capture into transport vesicles. Human proprotein convertase subtilisin/kexin type 9 (PCSK9) is a determinant of cholesterol metabolism whose secretion is mediated by a specific cargo adaptor protein, SEC24A. We map a series of protein-protein interactions between PCSK9, its endoplasmic reticulum (ER) export receptor SURF4, and SEC24A that mediate secretion of PCSK9. We show that the interaction between SURF4 and SEC24A can be inhibited by 4-phenylbutyrate (4-PBA), a small molecule that occludes a cargo-binding domain of SEC24. This inhibition reduces secretion of PCSK9 and additional SURF4 clients that we identify by mass spectrometry, leaving other secreted cargoes unaffected. We propose that selective small-molecule inhibition of cargo recognition by SEC24 is a potential therapeutic intervention for atherosclerosis and other diseases that are modulated by secreted proteins.



COPII vesicles, ER export, membrane traffic, COP-Coated Vesicles, Endoplasmic Reticulum, Humans, Membrane Proteins, Phenylbutyrates, Proprotein Convertase 9, Protein Interaction Mapping, Protein Transport, Secretory Pathway, Vesicular Transport Proteins

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Proc Natl Acad Sci U S A

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Proceedings of the National Academy of Sciences
UKRI | Medical Research Council (MRC) (MRC_UP_1201/10)
UKRI | Medical Research Council (MRC) (BSF29)
HHS | National Institutes of Health (NIH) (R01GM117473)