Nature Structural & Molecular Biology 13, 121 - 130 (2006)
Published online: 15 January 2006; | doi:10.1038/nsmb1043
Structural definition of the F-actin–binding THATCH domain from HIP1RTom J Brett1, Valerie Legendre-Guillemin3, Peter S McPherson3
& Daved H Fremont1, 21
Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, Missouri 63110, USA. 2
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, Missouri 63110, USA. 3
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada.
Correspondence should be addressed to Daved H Fremont fremont@wustl.edu Huntingtin-interacting protein-1 related (HIP1R) has a crucial protein-trafficking role, mediating associations between actin and clathrin-coated structures at the plasma membrane and trans-Golgi network. Here, we characterize the F-actin–binding region of HIP1R, termed the talin-HIP1/R/Sla2p actin-tethering C-terminal homology (THATCH) domain. The 1.9-Å crystal structure of the human HIP1R THATCH core reveals a large sequence-conserved surface patch created primarily by residues from the third and fourth helices of a unique five-helix bundle. Point mutations of seven contiguous patch residues produced significant decreases in F-actin binding. We also show that THATCH domains have a conserved C-terminal latch capable of oligomerizing the core, thereby modulating F-actin engagement. Collectively, these results establish a framework for investigating the links between endocytosis and actin dynamics mediated by THATCH domain–containing proteins.
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