Journal of Biological Chemistry
Volume 280, Issue 43, 28 October 2005, Pages 36464-36473
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Molecular Basis of Cell and Developmental Biology
Huntingtin Associates with Acidic Phospholipids at the Plasma Membrane*

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We have identified a domain in the N terminus of huntingtin that binds to membranes. A three-dimensional homology model of the structure of the binding domain predicts helical HEAT repeats, which emanate a positive electrostatic potential, consistent with a charge-based mechanism for membrane association. An amphipathic helix capable of inserting into pure lipid bilayers may serve to anchor huntingtin to the membrane. In cells, N-terminal huntingtin fragments targeted to regions of plasma membrane enriched in phosphatidylinositol 4,5-bisphosphate, receptor bound-transferrin, and endogenous huntingtin. N-terminal huntingtin fragments with an expanded polyglutamine tract aberrantly localized to intracellular regions instead of plasma membrane. Our data support a new model in which huntingtin directly binds membranes through electrostatic interactions with acidic phospholipids.

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The amino acid sequence of this protein can be accessed through NCBI Protein Database under NCBI accession numbers NP_002102, P51111, BAA36752, P42859, AAC63983, and P5111.

*

This work was supported by National Institutes of Health Grants NS16367 and NS35711 (to M. D.) and NS38194 (to N. A.), a grant from the Huntington's Disease Society of America Coalition (to M. D.), a grant from the Hereditary Disease Foundation (to K. B. K.), and Deutsch Forshungsgemeinschaft Grant Is 85/-1 and NATO (to W. H. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.