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Structural modeling of ataxin‐3 reveals distant homology to adaptins
Author(s) -
Albrecht Mario,
Hoffmann Daniel,
Evert Bernd O.,
Schmitt Ina,
Wüllner Ullrich,
Lengauer Thomas
Publication year - 2002
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.10280
Subject(s) - spinocerebellar ataxia , computational biology , homology modeling , trinucleotide repeat expansion , biology , protein structure , homology (biology) , gene , genetics , biochemistry , allele , enzyme
Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the coding region of a gene encoding ataxin‐3, a protein of yet unknown function. Based on a comprehensive computational analysis, we propose a structural model and structure‐based functions for ataxin‐3. Our predictive strategy comprises the compilation of multiple sequence and structure alignments of carefully selected proteins related to ataxin‐3. These alignments are consistent with additional information on sequence motifs, secondary structure, and domain architectures. The application of complementary methods revealed the homology of ataxin‐3 to ENTH and VHS domain proteins involved in membrane trafficking and regulatory adaptor functions. We modeled the structure of ataxin‐3 using the adaptin AP180 as a template and assessed the reliability of the model by comparison with known sequence and structural features. We could further infer potential functions of ataxin‐3 in agreement with known experimental data. Our database searches also identified an as yet uncharacterized family of proteins, which we named josephins because of their pronounced homology to the Josephin domain of ataxin‐3. Proteins 2003;50:355–370. © 2002 Wiley‐Liss, Inc.