These authors contributed equally to this work.
Crystal structure of the C-terminal domain of splicing factor Prp8 carrying retinitis pigmentosa mutants
Article first published online: 2 JAN 2009
Copyright © 2007 The Protein Society
Volume 16, Issue 6, pages 1024–1031, June 2007
How to Cite
Zhang, L., Shen, J., Guarnieri, M. T., Heroux, A., Yang, K. and Zhao, R. (2007), Crystal structure of the C-terminal domain of splicing factor Prp8 carrying retinitis pigmentosa mutants. Protein Science, 16: 1024–1031. doi: 10.1110/ps.072872007
- Issue published online: 2 JAN 2009
- Article first published online: 2 JAN 2009
- Manuscript Accepted: 24 MAR 2007
- Manuscript Revised: 23 MAR 2007
- Manuscript Received: 12 MAR 2007
- retinitis pigmentosa;
- MPN domain;
- crystal structure
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 α/β 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.