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.
Huntingtin associates with acidic phospholipids at the plasma membrane.,Kegel KB, Sapp E, Yoder J, Cuiffo B, Sobin L, Kim YJ, Qin ZH, Hayden MR, Aronin N, Scott DL, Isenberg G, Goldmann WH, DiFiglia M J Biol Chem. 2005 Oct 28;280(43):36464-73. Epub 2005 Aug 5. PMID:16085648
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Kegel KB, Sapp E, Yoder J, Cuiffo B, Sobin L, Kim YJ, Qin ZH, Hayden MR, Aronin N, Scott DL, Isenberg G, Goldmann WH, DiFiglia M. Huntingtin associates with acidic phospholipids at the plasma membrane. J Biol Chem. 2005 Oct 28;280(43):36464-73. Epub 2005 Aug 5. PMID:16085648 doi:10.1074/jbc.M503672200