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Crystal structure of the C-terminal domain of splicing factor Prp8 carrying retinitis pigmentosa mutants

¹ Department of Biochemistry and Molecular Genetics, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045, USA
² Biology Department, Brookhaven National Laboratory, Upton, New York 11973-5000, USA

(RECEIVED March 12, 2007; FINAL REVISION March 23, 2007; ACCEPTED March 24, 2007)

Prp8 is a critical pre-mRNA splicing factor. Prp8 is proposed to help form and stabilize the spliceosome catalytic core and to be an important regulator of spliceosome activation. Mutations in human Prp8 (hPrp8) cause a severe form of the genetic disorder retinitis pigmentosa, RP13. Understanding the molecular mechanism of Prp8’s function in pre-mRNA splicing and RP13 has been hindered by its large size (over 2000 amino acids) and remarkably low-sequence similarity with other proteins. Here we present the crystal structure of the C-terminal domain (the last 273 residues) of Caenorhabditis elegans Prp8 (cPrp8). The core of the C-terminal domain is an / structure that forms the MPN (Mpr1, Pad1 N-terminal) fold but without Zn²⁺ coordination. We propose that the C-terminal domain is a protein interaction domain instead of a Zn²⁺-dependent metalloenzyme as proposed for some MPN proteins. Mapping of RP13 mutants on the Prp8 structure suggests that these residues constitute a binding surface between Prp8 and other partner(s), and the disruption of this interaction provides a plausible molecular mechanism for RP13.

Keywords: Prp8; retinitis pigmentosa; MPN domain; crystal structure

Supplemental material: see www.proteinscience.org.

Reprint requests to: Rui Zhao, M.S. 8101, P.O. Box 6511, Aurora, CO 80045, USA; e-mail: rui.zhao{at}uchsc.edu; fax: (303) 724-3215.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.072872007.

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