Key result
N-terminal huntingtin fragments directly bind to plasma membranes through electrostatic interactions with acidic phospholipids, whereas fragments with expanded polyglutamine tracts aberrantly localize.
Huntingtin directly binds membranes through electrostatic interactions with acidic phospholipids, a process that is disrupted by expanded polyglutamine tracts.
Hypothesis-generating for polyglutamine toxicity; leaves open relevance to human disease mechanisms or therapies.
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.
No takes yet. Share an insight, caveat, or question.
Kegel et al. (2005) studied this question. N-terminal huntingtin fragments directly bind to plasma membranes through electrostatic interactions with acidic phospholipids, whereas fragments with expanded polyglutamine tracts aberrantly localize.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: