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 Å X-ray structure of the 219-residue N-terminal VHS and FYVE tandem domain unit of Drosophila Hrs. The unit assumes a pyramidal structure in which the much larger VHS domain (residues 1–153) forms a rectangular base and the FYVE domain occupies the apical end. The VHS domain is comprised of an unusual “superhelix” of eight α helices, and the FYVE domain is mainly built of loops, two double-stranded antiparallel sheets, and a helix stabilized by two tetrahedrally coordinated zinc atoms. The two-domain structure forms an exact 2-fold-related homodimer through antiparallel association of mainly FYVE domains. Dimerization creates two identical pockets designed for binding ligands with multiple negative charges such as citrate or phosphatidylinositol 3-phosphate.