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An estimated 2.000.000 people worldwide suffer from Retinitis pigmentosa, an inheritable disease characterized by the progressive degeneration of the retina that often leads to blindness in late stages. Researchers at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, have traced the molecular basis of a particular form of Retinitis pigmentosa to an aberrant communication between molecules that are part of a central cellular machinery in gene expression, the spliceosome. (Molecular Cell, February 23, 2007)
Retinitis pigmentosa refers to a group of inheritable diseases, characterized by a slow, progressive destruction of the retina, which eventually results in virtual blindness. With about one in every 2500 - 3500 individuals affected by the disorder, Retinitis pigmentosa is one of the most frequent causes for the loss of vision. Presently, there are no surgical or medicinal remedies available.
By now, a large body of evidence suggests that Retinitis pigmentosa correlates with defects in an essential cellular process, referred to as pre-mRNA splicing. In higher organisms, the majority of genes encoded on the DNA in the nucleus of a cell are mosaic; i.e. regions that carry information on how to construct a part of a protein molecule are interrupted by regions that do not bear any protein-coding information. In order to produce proteins based on the genetic information of a gene, an RNA copy of the DNA is produced. Initially, this 'pre-mRNA' contains both coding and non-coding stretches. Before it can be passed from the nucleus to the cytoplasm, where it is read like an instruction manual for building of proteins, the non-coding stretches have to be removed ('spliced') and the coding sections have to be pasted together. Pre-mRNA splicing is carried out by a complex, molecular machinery, the spliceosome, an assembly of well over 100 protein and RNA molecules. Patients affected by Retinitis pigmentosa often carry mutations, i.e. changes in the amino acid sequence, in one of the protein building blocks of the spliceosome.
The largest protein of the spliceosome, Prp8, physically interacts with many other functionally important molecular parts of the splicing machinery. Indeed, Prp8 is envisioned as an assembly platform for other protein and RNA factors involved in this process. Mutations that occur in patients affected with RP13, a particularly severe form of Retinitis pigmentosa, cumulate at one end of this giant molecule. With the method of X-ray crystallography members of the research groups of Markus Wahl and Reinhard Lührmann from the Max-Planck-Institute for Biophysical Chemistry in Göttingen (Germany) have now succeeded in visualizing the three-dimensional atomic structure of this part of Prp8 (Figure). For this purpose, the team produced milligram amounts of the protein by genetically engineering a bacterium, Escherichia coli. From this recombinant material they were able to grow crystals, i.e. ordered molecular arrays. Upon exposure to focused, monochromatic X-rays, such crystals give rise to diffraction patterns from which the exact atomic arrangement in the crystals can be calculated.
The atomic structure of the protein revealed that all amino acids, which are altered in patients suffering from RP13, cluster in an extended appendage at one end of the molecule (Figure). Using method that is based on molecular genetics in Baker's yeast, the researchers probed the function of this appendage. Upon complete removal of this section, two other protein constituents of the spliceosome, which normally attach to this part of Prp8, could no longer bind. When the team introduced point mutations, i.e. changes in single amino acids, as found in RP13 patients, they observed a reduced affinity of the two other proteins to Prp8. These results showed that the terminal appendage of Prp8 constitutes an important interaction site for certain protein molecules of the spliceosome, comparable to a clothesline for hanging several pieces of laundry. When this docking site is dysfunctional, as in RP13, the splicing machinery could malfunction in the production of a retina-specific protein.
These results for the first time trace a particular form of Retinitis pigmentosa to an aberrant molecular communication in an essential cellular machinery. While these findings do not directly provide a route for treatment of the disease, the detailed understanding of the molecular basis of Retinitis pigmentosa may in the future contribute to ideas for a remedy.
Original Publication:
Vladimir Pena, Sunbin Liu, Janusz M. Bujnicki, Reinhard Lührmann, and Markus C. Wahl: Structure of a Multipartite Protein-Protein Interaction Domain in Splicing Factor Prp8 and its Link to Retinitis Pigmentosa. Molecular Cell 25, 615-624 (February 23, 2007), doi: 10.1016/j.molcel.2007.01.023
For further information contact:
Dr. Markus Wahl, Max Planck Institute for Biophysical Chemistry, Res. Group X-Ray Crystallography, Am Fassberg 11, 37077 Göttingen, Germany. Tel: +49 551 201-1046, Fax: -1197, e-mail: mwahl@gwdg.de
www.mpibpc.mpg.de/groups/wahl/
Prof. Dr. Reinhard Lührmann, Max Planck Institute for Biophysical Chemistry, Dept. Cellular Biochemistry, Am Fassberg 11, 37077 Göttingen, Germany. Tel: +49 551 201-1405, Fax: -1197, e-mail: reinhard.luehrmann@mpi-bpc.mpg.de
www.mpibpc.gwdg.de/research/dep/luehrmann/
http://www.mpibpc.mpg.de/groups/pr/PR/2007/07_06/index_en.html - this PR
Structure of the terminal part of the protein Prp8. Different architectural elements are shown in di ...
Markus Wahl, MPI for Biophysical Chemistry
None
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Structure of the terminal part of the protein Prp8. Different architectural elements are shown in di ...
Markus Wahl, MPI for Biophysical Chemistry
None
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