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Recipient: Valérie Legendre-Guillemin - Biosketch Articles: Metzler M*, Legendre-Guillemin V*, Gan L, Chopra V, Kwok A, McPherson PS and Hayden MR. (2001) HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2. J Biol Chem. 276(42):39271-39276. (*Both authors contributed equally to this work). Legendre-Guillemin, V.*, Metzler, M.*, Charbonneau, M., Gan, L., Chopra, V., Philie, J., Hayden, M.R. and McPherson, P.S., (2002) HIP1 and HIP12 Display Differential Binding to F-actin, AP2, and Clathrin. J. Biol. Chem. 277:19897-19904. (*Both authors contributed equally to this work). |
Brain Star - July 1, 2003Significance of Research:
Polyglutamine expansion in huntingtin is the underlying mutation leading to neurodegeneration in Huntington's Disease. This disease is cell-type specific since neuronal degeneration occurs predominantly in medium spiny projection neurons. The cell-type specificity in HD seems to result from alterations in the interaction of huntingtin with protein partners and is not simply a reflection of the abundance of huntingtin in striatal neurons. Since the function of huntingtin has remained elusive, we sought to identify its interacting proteins to obtain information about the cellular mechanisms that could be altered in HD. We analyzed the function of huntingtin interacting protein 1 (HIP1) which shows profoundly reduced interaction with mutant huntingtin. In the present two studies, we demonstrate that HIP1 is an endocytic protein. HIP1 binds directly to clathrin and AP2 and it has an inherent clathrin assembly activity. We also show that many of the endocytic properties of HIP1 are shared with its family member HIP12, including the ability to assemble clathrin through its coiled-coil domain. However, unlike HIP1, HIP12 does not bind directly to huntingtin. Finally, we provide evidence that both proteins can influence each others function through heterodimerization, that is also mediated through both their coiled-coil domains.
The finding that HIP1 plays a role in endocytosis has profound implications for the functional analysis of huntingtin and our understanding of HD. Our results provide a concrete platform for studying the role of huntingtin in clathrin-mediated endocytosis and how mutant huntingtin may influence this process. We can directly test the hypothesis that HD results from a dysregulation in endocytosis since a YAC transgenic mouse model for HD has been generated in the Hayden lab. These studies gain in importance since huntingtin interacts with two other endocytic proteins, the adaptor protein AP2 and the accessory endocytic protein endophilin. Furthermore, recent studies have shown that other huntingtin interacting proteins play roles in intracellular transport in vitro. The idea that HD results from multiple defects in intracellular transport becomes more testable and is encouraged by our analysis of HIP1.
