MBE Advance Access published online on November 28, 2007
Molecular Biology and Evolution, doi:10.1093/molbev/msm258
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Research Article |
Phylogenetic Comparison of Huntingtin Homologues Reveals the Appearance of a Primitive PolyQ in Sea Urchin
(1) Department of Pharmacological Sciences, University of Milan, Italy
(2) Department of Biomolecular Sciences and Biotechnology, University of Milan, Italy
(3) Department of Biochemistry and Molecular Biology, University of Bari and CNR Biomedical Technology Institute, Bari, Italy
* co-corresponding authors and co-last authors: Elena Cattaneo, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milano, Italy. Tel. 02-50318333; fax02-50318284; e-mail elena.cattaneo{at}unimi.it, Graziano Pesole, Department of Biochemistry and Molecular Biology, University of Bari and CNR Biomedical Technology Institute, Bari, Italy.,Tel.080-5443588; fax080-5443317; email graziano.pesole{at}biologia.uniba.it
Received for publication August 29, 2007. Revision received October 19, 2007. Accepted for publication November 18, 2007.
Huntingtin is a completely soluble 3144 amino acid protein characterised by the presence of an amino-terminal polymorphic polyglutamine (polyQ) tract whose aberrant expansion causes the progressively neurodegenerative Huntington's disease (HD). Biological evidence indicates that huntingtin is beneficial to cells (particularly to brain neurons) and that loss of its neuronal function may contribute to HD. The exact protein domains involved in its neuroprotective function are unknown. Evolutionary analyses of huntingtin primary amino acids have so far been limited to a few species, but its thorough assessment may help to clarify the functions emerging during evolution. We made an extensive comparative analysis of the available huntingtin protein homologues from different organisms along the metazoan phylogenetic tree, and defined the presence of three different conservative blocks corresponding to human huntingtin aa 1-386 (htt1), 683-1586 (htt2) and 2437-3078 (htt3), in which HEAT repeats are well conserved. We also describe the cloning and sequencing of sea urchin huntingtin mRNA, the oldest deuterostome homologue so far available. Multiple alignment shows the first appearance of a primitive polyQ in sea urchin, which predates an ancestral polyQ sequence in a non-chordate environment and defines the polyQ characteristic as being typical of the deuterostome branch. The fact that glutamines have conserved positions in deuterostomes and the polyQ size increases during evolution suggests that the protein has a possibly Q-dependent role. Finally, we report an evident relaxing constraint of the N-terminal block in Ciona and drosophilids that correlates with the absence of polyQ, and which may indicate that the N-terminal portion of huntingtin has evolved different functions in Ciona and protostomes.
Key Words: Huntingtin • polyQ • sea urchin • evolution • homologues • deuterostomes
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