Structure of the Dual Enzyme Ire1 Reveals the Basis for Catalysis and Regulation in Nonconventional RNA Splicing

Kenneth P.K. Lee, Madhusudan Dey, Dante Neculai, Chune Cao, Thomas E. Dever, Frank Sicheri

Research output: Contribution to journalArticle

206 Citations (Scopus)

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 Å 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.

Original languageEnglish (US)
Pages (from-to)89-100
Number of pages12
JournalCell
Volume132
Issue number1
DOIs
StatePublished - Jan 11 2008

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RNA Splicing
Ribonucleases
Catalysis
RNA
Dimerization
Enzymes
Protein Kinases
Catalytic Domain
Phosphotransferases
Spliceosomes
Fusion reactions
Nucleotides
Crystal structure
Messenger RNA
Sensors

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lee, Kenneth P.K. ; Dey, Madhusudan ; Neculai, Dante ; Cao, Chune ; Dever, Thomas E. ; Sicheri, Frank. / Structure of the Dual Enzyme Ire1 Reveals the Basis for Catalysis and Regulation in Nonconventional RNA Splicing. In: Cell. 2008 ; Vol. 132, No. 1. pp. 89-100.
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Structure of the Dual Enzyme Ire1 Reveals the Basis for Catalysis and Regulation in Nonconventional RNA Splicing. / Lee, Kenneth P.K.; Dey, Madhusudan; Neculai, Dante; Cao, Chune; Dever, Thomas E.; Sicheri, Frank.

In: Cell, Vol. 132, No. 1, 11.01.2008, p. 89-100.

Research output: Contribution to journalArticle

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