Article abstract
Nature Structural & Molecular Biology 16, 731 - 739 (2009)
Published online: 14 June 2009 | doi:10.1038/nsmb.1625
Structural evidence for consecutive Hel308-like modules in the spliceosomal ATPase Brr2
Lingdi Zhang1, Tao Xu1, Corina Maeder2, Laura-Oana Bud3, James Shanks1, Jay Nix4, Christine Guthrie2, Jeffrey A Pleiss3 & Rui Zhao1
Abstract
Brr2 is a DExD/H-box helicase responsible for U4/U6 unwinding during spliceosomal activation. Brr2 contains two helicase-like domains, each of which is followed by a Sec63 domain with unknown function. We determined the crystal structure of the second Sec63 domain, which unexpectedly resembles domains 4 and 5 of DNA helicase Hel308. This, together with sequence similarities between Brr2's helicase-like domains and domains 1–3 of Hel308, led us to hypothesize that Brr2 contains two consecutive Hel308-like modules (Hel308-I and Hel308-II). Our structural model and mutagenesis data suggest that Brr2 shares a similar helicase mechanism with Hel308. We demonstrate that Hel308-II interacts with Prp8 and Snu114 in vitro and in vivo. We further find that the C-terminal region of Prp8 (Prp8-CTR) facilitates the binding of the Brr2–Prp8-CTR complex to U4/U6. Our results have important implications for the mechanism and regulation of Brr2's activity in splicing.
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, Colorado, USA.
- Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA.
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA.
- Molecular Biology Consortium, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
Correspondence to: Rui Zhao1 e-mail: rui.zhao@ucdenver.edu
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