What’s Your Favorite Crystal Structure?
نویسندگان
چکیده
I stumbled into the crystal structure of Ire1 a few years ago when my lab had just solved the structures of several helical signaling oligomers formed by death domains. I was curious if others had observed similar structures in their systems andwhether these higher-order oligomers might tell us something new about molecular mechanisms in signal transduction. Ire1 is a receptor critical for the unfolded protein response (UPR) in the endoplasmic reticulum (ER). It contains an ER luminal region that senses aberrantly folded proteins and a cytoplasmic region with a kinase domain and an RNase domain. Upon activation, the Ire1 RNase mediates nonconventional mRNA splicing to enable expression of transcriptional factors that activate the UPR. The crystal structure of the Ire1 cytosolic domain reveals a striking oligomeric assembly, corroborating the observed activation of the Ire1 RNase in solution by oligomerization (Nature [2009]. 457, 687–693). Symmetric back-to-back Ire1 dimers arrange into a filament through helical symmetry. Each kinase domain extends its activation loop to the next kinase domain, resembling a trans-autophosphorylation reaction. Remarkably, the RNase active site that is disordered in a dimer structure becomes ordered in the oligomer to create the mRNA-binding pocket. The oligomerization-promoted allosteric activation of the RNase made perfect sense to me, and an analogous mechanism may bring about kinase and caspase activation in the context of innate immune signaling. A picture is worth a thousand words. A Single Base Pair
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عنوان ژورنال:
- Cell
دوره 159 شماره
صفحات -
تاریخ انتشار 2014