|1yzb, 10 NMR models ()|
Solution structure of the Josephin domain of Ataxin-3
The Josephin domain plays an important role in the cellular functions of ataxin-3, the protein responsible for the neurodegenerative Machado-Joseph disease. We have determined the solution structure of Josephin and shown that it belongs to the family of papain-like cysteine proteases, sharing the highest degree of structural similarity with bacterial staphopain. A currently unique structural feature of Josephin is a flexible helical hairpin formed by a 32-residue insertion, which could determine substrate specificity. By using the Josephin structure and the availability of NMR chemical shift assignments, we have mapped the enzyme active site by using the typical cysteine protease inhibitors, transepoxysuccinyl-L-eucylamido-4-guanidino-butane (E-64) and [L-3-trans-(propylcarbamyl)oxirane-2-carbonyl]-L-isoleucyl-L-proline (CA-074). We also demonstrate that the specific interaction of Josephin with the ubiquitin-like domain of the ubiquitin- and proteasome-binding factor HHR23B involves complementary exposed hydrophobic surfaces. The structural similarity with other deubiquitinating enzymes suggests a model for the proteolytic enzymatic activity of ataxin-3.
The solution structure of the Josephin domain of ataxin-3: structural determinants for molecular recognition., Nicastro G, Menon RP, Masino L, Knowles PP, McDonald NQ, Pastore A, Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10493-8. Epub 2005 Jul 14. PMID:16020535
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
- Nicastro G, Menon RP, Masino L, Knowles PP, McDonald NQ, Pastore A. The solution structure of the Josephin domain of ataxin-3: structural determinants for molecular recognition. Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10493-8. Epub 2005 Jul 14. PMID:16020535
- Nicastro G, Masino L, Frenkiel TA, Kelly G, McCormick J, Menon RP, Pastore A. Assignment of the 1H, 13C, and 15N resonances of the Josephin domain of human ataxin-3. J Biomol NMR. 2004 Dec;30(4):457-8. PMID:15630566 doi:http://dx.doi.org/10.1007/s10858-004-4343-3
- Masino L, Nicastro G, Menon RP, Dal Piaz F, Calder L, Pastore A. Characterization of the structure and the amyloidogenic properties of the Josephin domain of the polyglutamine-containing protein ataxin-3. J Mol Biol. 2004 Dec 3;344(4):1021-35. PMID:15544810 doi:http://dx.doi.org/10.1016/j.jmb.2004.09.065