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J Biol Chem. 2008 Aug 29;283(35):23950-5. doi: 10.1074/jbc.M800467200. Epub 2008 Jun 27.

A common motif targets huntingtin and the androgen receptor to the proteasome.

Author information

1
Departments of Neurology and Cellular and Molecular Pharmacology, University of California-San Francisco, 600 16th Street, San Francisco, CA 94143, USA.

Abstract

Huntington disease derives from a critically expanded polyglutamine tract in the huntingtin (Htt) protein; a similar polyglutamine expansion in the androgen receptor (AR) causes spinobulbar muscular atrophy. AR activity also plays an essential role in prostate cancer. Molecular mechanisms that regulate Htt and AR degradation are not well understood but could have important therapeutic implications. We find that a pentapeptide motif (FQKLL) within the Htt protein regulates its degradation and subcellular localization to cytoplasm puncta. Disruption of the motif by alanine substitution at the hydrophobic residues increases the steady state level of the protein. Pulsechase analyses indicate that the motif regulates degradation. A similar motif (FQNLF) has corresponding activities in the AR protein. Transfer of the Htt motif with five flanking amino acids on either side to YFP reduces the steady state YFP level by rendering it susceptible to proteasome degradation. This work defines a novel proteasome-targeting motif that is necessary and sufficient to regulate the degradation of two disease-associated proteins.

PMID:
18586675
PMCID:
PMC2527109
DOI:
10.1074/jbc.M800467200
[Indexed for MEDLINE]
Free PMC Article

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