Crystal structure of the VHS and FYVE tandem domains of Hrs, a protein involved in membrane trafficking and signal transduction

We have determined the 2 Angstrom X-ray structure of the 219-residue N-term inal VHS and MIE tandem domain unit of Drosophila Hrs. The unit assumes a p yramidal structure in which the much larger YHS domain (residues 1-153) for ms a rectangular base and the FYVE domain occupies the apical end. The VHS domain is comprised of an unusual "superhelix" of eight alpha helices, and the MIE domain is mainly built of loops, two double-stranded antiparallel s heets, and a helix stabilized by two tetrahedrally coordinated zinc atoms. The two-domain structure forms an exact 2-fold-related homodimer through an tiparallel association of mainly FYVE domains. Dimerization creates two ide ntical pockets designed for binding ligands with multiple negative charges such as citrate or phosphatidylinositol 3-phosphate.