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Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing. Cell 2008 Jan 11;132(1):89-100

Date

01/15/2008

Pubmed ID

18191223

Pubmed Central ID

PMC2276645

DOI

10.1016/j.cell.2007.10.057

Scopus ID

2-s2.0-37649004940 (requires institutional sign-in at Scopus site)   311 Citations

Abstract

Ire1 is an ancient transmembrane sensor of ER stress with dual protein kinase and ribonuclease activities. In response to ER stress, Ire1 catalyzes the splicing of target mRNAs in a spliceosome-independent manner. We have determined the crystal structure of the dual catalytic region of Ire1at 2.4 A resolution, revealing the fusion of a domain, which we term the KEN domain, to the protein kinase domain. Dimerization of the kinase domain composes a large catalytic surface on the KEN domain which carries out ribonuclease function. We further show that signal induced trans-autophosphorylation of the kinase domain permits unfettered binding of nucleotide, which in turn promotes dimerization to compose the ribonuclease active site. Comparison of Ire1 to a topologically disparate ribonuclease reveals the convergent evolution of their catalytic mechanism. These findings provide a basis for understanding the mechanism of action of RNaseL and other pseudokinases, which represent 10% of the human kinome.

Author List

Lee KP, Dey M, Neculai D, Cao C, Dever TE, Sicheri F

Author

Madhusudan Dey PhD Assistant Professor in the Biological Sciences department at University of Wisconsin - Milwaukee




MESH terms used to index this publication - Major topics in bold

Alternative Splicing
Amino Acid Sequence
Binding Sites
Catalytic Domain
Crystallography, X-Ray
Dimerization
Endoplasmic Reticulum
Evolution, Molecular
Membrane Glycoproteins
Models, Molecular
Molecular Sequence Data
Nucleotides
Oxidative Stress
Phosphorylation
Phosphotransferases
Protein Binding
Protein Conformation
Protein Folding
Protein Structure, Tertiary
RNA, Messenger
Ribonucleases
Saccharomyces cerevisiae Proteins
Sequence Homology, Amino Acid
Yeasts