title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takano
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
mesh_terms: 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*
chemical_list: 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