Just came back from Dr. Alexei Korennykh's talk. He was awarded for 2010 Dean's Postdoctoral Prize in UCSF.
The presentation is very good, of course the science is great! I stayed awaken the entire lecture. Really amazed by the mechanism he found.
In the middle of last year, his mentor Dr. Peter Walter has already presented the data in a seminar. It is when I initially amazed by this oligomerization driven sensitivity.
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Their Ire1 oligomer function model is very like a car engine: one dimer as a function unit, and dimers are at different activity states to exert functions (Alexei showed an engine model from Hiller Museum to help the audience to understand the Ire1 oligomer).
The most amazing part of their model is that with oligomerization, Hill coefficient increases from 2 to 3.5-8, which enables the cell to sense unfolded protein timely, such as 70% increase, to trigger the response!
Nature. 2009 Feb 5;457(7230):687-93. Epub 2008 Dec 14.
The unfolded protein response signals through high-order assembly of Ire1.
Korennykh AV, Egea PF, Korostelev AA, Finer-Moore J, Zhang C, Shokat KM, Stroud RM, Walter P.
Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94158, USA. alexei.korennykh@ucsf.edu
Aberrant folding of proteins in the endoplasmic reticulum activates the bifunctional transmembrane kinase/endoribonuclease Ire1. Ire1 excises an intron from HAC1 messenger RNA in yeasts and Xbp1 messenger RNA in metozoans encoding homologous transcription factors. This non-conventional mRNA splicing event initiates the unfolded protein response, a transcriptional program that relieves the endoplasmic reticulum stress. Here we show that oligomerization is central to Ire1 function and is an intrinsic attribute of its cytosolic domains. We obtained the 3.2-A crystal structure of the oligomer of the Ire1 cytosolic domains in complex with a kinase inhibitor that acts as a potent activator of the Ire1 RNase. The structure reveals a rod-shaped assembly that has no known precedence among kinases. This assembly positions the kinase domain for trans-autophosphorylation, orders the RNase domain, and creates an interaction surface for binding of the mRNA substrate. Activation of Ire1 through oligomerization expands the mechanistic repertoire of kinase-based signalling receptors.
Congratulations Alexei!
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