Structure validation of the Josephin domain of ataxin-3: Conclusive evidence for an open conformation

• DOI: 10.1007/s10858-006-9092-z
• Publication Date: 2006-11-09T10:20:55Z
• Authors: Giuseppe Nicastro; Michael Habeck; Laura Masino; Dmitri I. Svergun; Annalisa Pastore
• Keywords: 0301 basic medicine; 570; Protein Folding; Ubiquitin; Molecular Conformation; 610; Nuclear Proteins; Quantitative Structure-Activity Relationship; Bayes Theorem; Nerve Tissue Proteins; Protein Structure, Secondary; Protein Structure, Tertiary; Repressor Proteins; 03 medical and health sciences; Ataxin-3; Protein Structure, Quaternary

The availability of new and fast tools in structure determination has led to a more than exponential growth of the number of structures solved per year. It is therefore increasingly essential to assess the accuracy of the new structures by reliable approaches able to assist validation. Here, we discuss a specific example in which the use of different complementary techniques, which include Bayesian methods and small angle scattering, resulted essential for validating the two currently available structures of the Josephin domain of ataxin-3, a protein involved in the ubiquitin/proteasome pathway and responsible for neurodegenerative spinocerebellar ataxia of type 3. Taken together, our results demonstrate that only one of the two structures is compatible with the experimental information. Based on the high precision of our refined structure, we show that Josephin contains an open cleft which could be directly implicated in the interaction with polyubiquitin chains and other partners.