The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with dorsal, an NF-kB/Rel/dorsal family transcription factor.
BACKGROUND
Huntington's disease (HD) pathogenesis is due to an expanded polyglutamine tract in huntingtin, but the specificity of neuronal loss compared with other polyglutamine disorders also implies a role for the protein's unknown inherent function. Huntingtin is moderately conserved, with 10 HEAT repeats reported in its amino-terminal half. HD orthologues are evident in vertebrates and Drosophila, but not in Saccharomyces cerevisiae, Caenorhabditis elegans or Arabidopsis thaliana, a phylogenetic profile similar to the NF-kB/Rel/dorsal family transcription factors, suggesting a potential functional relationship.


RESULTS
We initially tested the potential for a relationship between huntingtin and dorsal by overexpression experiments in Drosophila S2 cells. Drosophila huntingtin complexes via its carboxyl-terminal region with dorsal, and the two enter the nucleus concomitantly, partly in a lipopolysaccharide (LPS)- and Nup88-dependent manner. Similarly, in HeLa cell extracts, human huntingtin co-immunoprecipitates with NF-kB p50 but not with p105. By cross-species comparative analysis, we find that the carboxyl-terminal segment of huntingtin that mediates the association with dorsal possesses numerous HEAT-like sequences related to those in the amino-terminal segment. Thus, Drosophila and vertebrate huntingtins are composed predominantly of 28 to 36 degenerate HEAT-like repeats that span the entire protein.


CONCLUSIONS
Like other HEAT-repeat filled proteins, huntingtin is made up largely of degenerate HEAT-like sequences, suggesting that it may play a scaffolding role in the formation of particular protein-protein complexes. While many proteins have been implicated in complexes with the amino-terminal region of huntingtin, the NF-kB/Rel/dorsal family transcription factors merit further examination as direct or indirect interactors with huntingtin's carboxyl-terminal segment.
Takano
Hiroki
H
Molecular Neurogenetics Unit, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, MGH-East Building 149, 13th Street, Charlestown, Massachusetts 02129, USA. hiroki@bri.niigata-u.ac.jp
Gusella
James F
JF
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D017124:Conserved Sequence; D004330:Drosophila; D029721:Drosophila Proteins; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D008070:Lipopolysaccharides / Q000494:pharmacology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding / Q000502:physiology; D017368:Protein Prenylation / Q000502:physiology; D020449:Repetitive Sequences, Amino Acid / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
D029721:Drosophila Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D008070:Lipopolysaccharides; D016328:NF-kappa B; C104835:NUP88 protein, human; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D014157:Transcription Factors; C062236:dl protein, Drosophila; C491301:mbo protein, Drosophila