tailieunhanh - Báo cáo khoa học: Structural and functional analysis of ataxin-2 and ataxin-3

Spinocerebellar ataxia types 2 (SCA2) and 3 (SCA3) are autosomal-dominantly inherited, neurodegenerative dis-eases caused by CAG repeat expansions in the coding regions of the genes encoding ataxin-2 and ataxin-3, respectively. To provide a rationale for further functional experiments, we explored the proteinarchitectures of ataxin-2 and ataxin-3. Using structure-based multiple sequence alignments of homologous proteins, we investigated domains, sequence motifs, and interaction partners. Our analyses focused on presumably functional amino acids and the construction of tertiary structure models of the RNA-binding Lsm domain of ataxin-2 and the deubiquitinating Josephin domain of ataxin-3 | Eur. J. Biochem. 271 3155-3170 2004 FEBS 2004 doi Structural and functional analysis of ataxin-2 and ataxin-3 Mario Albrecht1 Michael Golatta2 Ullrich Wiillner3 and Thomas Lengauer1 1 Max-Planck-Institute for Informatics Saarbrucken Germany 2Institute for Medical Biometry Informatics and Epidemiology University of Bonn Germany Department of Neurology University of Bonn Germany Spinocerebellar ataxia types 2 SCA2 and 3 SCA3 are autosomal-dominantly inherited neurodegenerative diseases caused by CAG repeat expansions in the coding regions of the genes encoding ataxin-2 and ataxin-3 respectively. To provide a rationale for further functional experiments we explored the protein architectures of ataxin-2 and ataxin-3. Using structure-based multiple sequence alignments of homologous proteins we investigated domains sequence motifs and interaction partners. Our analyses focused on presumably functional amino acids and the construction of tertiary structure models of the RNA-binding Lsm domain of ataxin-2 and the deubiquitinating Josephin domain of ataxin-3. We also speculate about distant evolutionary relationships of ubiquitin-binding UIM GAT UBA and CUE domains and helical ANTH and UBX domain extensions. Keywords spinocerebellar ataxia Machado-Joseph disease polyglutamine disorder ubiquitin valosin-containing protein. Spinocerebellar ataxia types 2 SCA2 and 3 SCA3 are autosomal-dominantly inherited neurodegenerative disorders 1 2 . SCA3 has also been known as Machado-Joseph disease MJD and SCA2 and SCA3 belong to a heterogeneous group of trinucleotide repeat disorders. This group includes Huntington disease HD dentatorubral-pallidoluysian atrophy DRPLA and other spinocerebellar ataxia types such as SCA1 SCA7 and SCA17 3-7 . The age of onset of SCA2 and SCA3 is in the third to fourth decade 8 . The disorders share common phenotypic features such as the degeneration of specific vulnerable neuron populations and the presence of .