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♦ See referenced article, J. Biol. Chem. 2010, 285, 9962–9970
In Saccharomyces cerevisiae, Get3, Get4, and Get5 participate in anchoring proteins to the membrane of the endoplasmic reticulum. Mass spectrometry and yeast two-hybrid assays indicate that these three Get proteins, along with a tetratricopeptide repeat-containing protein called Sgt2, all interact with one another in some fashion. Now, in this Paper of the Week, Yi-Wei Chang and colleagues report that they have elucidated how these proteins interact, using co-immunoprecipitation and structural approaches. They have found that Get4 and Get5 form a tight 1:1 complex mediated by hydrophobic bonds, suggesting they are both subunits of a larger complex. In addition, the Get4-Get5 crystal structure revealed that Get4 may play an important role in stabilizing Get5, because the N-terminal domain of Get5 would be exposed and at risk of proteolytic cleavage when not complexed with Get4. In contrast, both Get3 and Sgt2 exhibited lower and non-stoichiometric interactions with Get4-Get5, suggesting that Get3 and Sgt2 associations with Get4-Get5 are transient and varied. Chang and colleagues also found that Get3, Get4, and Get5 interact with the molecular chaperone Ydj1, indicating that chaperones may also be involved in inserting proteins into the endoplasmic membrane. The results of this thorough study provide a deeper understanding of the machinery and process involved in targeting tail-anchored proteins to their destination.