Crystal Structure of the VHS and FYVE Tandem Domains of Hrs, a Protein Involved in Membrane Trafficking and Signal Transduction

Department of Biochemistry & Molecular Biology, Baylor College of Medicine, Houston, Texas, United States
Cell (Impact Factor: 32.24). 03/2000; 100(4):447-56. DOI: 10.1016/S0092-8674(00)80680-7
Source: PubMed


We have determined the 2 A 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 alpha 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.

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    • "The Vps - 27 , Hrs , and STAM ( VHS ) domain is structurally very similar to the ENTH domain , and the ENTH , ANTH , and VHS proteins are often treated as a superfamily ( Interpro IPR008942=ENTH / VHS ) . Similar to the ENTH domain , the VHS domain contains eight a - helices and is ; 150 amino acids in length ( Mao et al . , 2000 ) . Proteins with a VHS domain often have other functionally important structured domains and can be grouped accordingly ( for an overview , see Lohi et al . , 2002 ) . Members of one such group contain the Fab - 1 , YGL023 , Vps27 , and EEA1 ( FYVE ) domain , which is required for PtdIns ( 3 ) P binding at the animal early endosome ( E"
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    • "The ∝ − helices of the ENTH, ANTH and VHS domains were localized on the Multiple Alignment of Complete Sequences (MACS) based on the protein structures found in the PDB database. Structure of TOM is 1ELK [24], VHS is 1DVP [8], Epsin1 is 1INZ [55], GGA1 is 1JWF [25], CALM is 1HF8 [9] and STAM is 1X5B (by Tochio, N., Koshiba, S., Inoue, M., Kigawa, T. and Yokoyama, S. for the RIKEN Structural Genomics/Proteomics Initiative (RSGI)). "
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    • "The ESCRT-0 complex consists of two subunits, Hrs (Vps27 in yeast) and STAM1/2 (Hse1 in yeast). Hrs contains a FYVE zinc finger domain which binds PtdIns(3)P providing membrane recruitment and endosomal specificity for the ESCRT-0 complex (Mao et al., 2000). Hrs and STAM1/2 bind ubiquitin via their UIM and VHS ubiquitin domains respectively, which are essential for efficient sorting of ubiquitinated proteins (Bishop et al., 2002; Mizuno et al., 2003; Bache et al., 2006). "

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