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Structural evidence for consecutive Hel308-like modules in the spliceosomal ATPase Brr2.

  • Author(s): Zhang, Lingdi
  • Xu, Tao
  • Maeder, Corina
  • Bud, Laura-Oana
  • Shanks, James
  • Nix, Jay
  • Guthrie, Christine
  • Pleiss, Jeffrey A
  • Zhao, Rui
  • et al.

Published Web Location

https://doi.org/10.1038/nsmb.1625
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.

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