Mammalian cells secrete a plethora of different proteins such as antibodies, hormones and blood proteins that fulfill their biological function outside the cell. The process of protein secretion starts in the endoplasmic reticulum, a specialized cellular organelle where secretory proteins are synthesized, correctly folded, and sorted into transport vesicles. Efficient packaging of secretory proteins into transport vesicles requires the assistance of so called cargo receptors.
Beat Nyfeler and Hans-Peter Hauri addressed the mechanism of how secretory proteins enter transport vesicles by analyzing the mammalian cargo receptor ERGIC-53. ERGIC-53 is a transmembrane receptor that assists a subset of glycoproteins, including blood coagulation factors V and VIII, in efficient secretion.
To identify novel ERGIC-53 cargo proteins, the scientists developed a genome-wide screening approach based on the complementation of the yellow fluorescent protein (YFP) in living cells. By screening a human liver cDNA library, they identified a1-antitrypsin as previously unrecognized ERGIC-53 cargo protein. a1-antitrypsin is an important liver glycoprotein that is secreted into the blood where it acts as a serine protease inhibitor. Mutations in a1-antitrypsin can cause severe liver and lung diseases in humans.
In their follow up experiments, Nyfeler and Hauri found that the secretion of a1-antitrypsin is significantly delayed in ERGIC-53 knockdown and knockout cells. Interestingly, ERGIC-53 did not bind misfolded mutants of a1-antitrypsin that are known to cause liver and lung diseases in humans. This finding suggests that ERGIC-53 functions in protein quality control, ensuring that only correctly folded a1-antitrypsin is secreted by the liver cells. The novel YFP complementation assay has a promising potential for high-throughput screening of chemicals that can rescue conformational defects of a1-antitrypsin.
In this study Nyfeler and Hauri clearly identified ERGIC-53 as an intracellular cargo receptor of a1-antitrypsin and demonstrated the feasibility of YFP complementation-based cDNA library screening to identify novel protein complexes. Their work is the first successful screening method for the identification of protein complexes in the secretory pathway of living cells on a genome-wide scale.Source article
Alexandra Weber | alfa
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