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FYVE Domain
Class:Phospholipid Binding

No Image The crystal structure of the FYVE domain from the yeast protein Vps27p (shown here) consists of a long loop at the very N-terminus followed by two Zn2+ binding clusters, two pairs of double stranded antiparallel beta sheets and a C-terminal alpha helix. Its two Zn2+ binding clusters and a small hydrophobic core stabilize the structure. The core secondary structure elements and one of the two Zn2+ binding clusters are superimposable with other small Zn2+ binding domains including the DNA binding domain of GATA-1, the C1 domain of protein kinase C, and the LIM domain. A compact, predominantly basic, PI(3)P binding pocket is formed by a highly conserved RKHHCR motif at the tip of the first beta strand. The pocket is too small to bind an inositol bis- or tris-phosphate, explaining the absence of binding to PI(3,4)P2, PI(4,5)P2, PI(3,5)P2, and PIP3. Furthermore, a hydrophobic protrusion formed by Leu-185 and Leu 186 is predicted to be membrane proximal and function as a site for hydrophobic penetration into the lipid bilayer.

Structure Reference:
Misra, S. et al. (1999) Cell. 97(5): 657-66. PDB: 1VFY.

Domain binding and function:
The FYVE (Fab-1, YGL023, Vps27, and EEA1) domain is a small, cysteine-rich Zn2+ binding domain of approximately 60-70 amino acids. To date, FYVE domains have been identified in over 300 different proteins from yeast to man. The FYVE domain structure consists of two β-hairpins plus a small C-terminal α-helix held together by two Zn2+ binding clusters. FYVE domains contains a basic motif in the first β-strand (R/K)(R/K)HHCR, creating a positively charged pocket shown to specifically bind PI(3)P. Upon binding of the FYVE domain to PI(3)P, a membrane insertion loop (MIL) located within the domain penetrates into the phospholipid bilayer. The EEA1 protein has an increased affinity for PI(3)P upon dimerization as well as lowered cytosolic pH. FYVE domain binding of PI(3)P has implicated it in a signaling role downstream of PI(3)kinase. Furthermore, FYVE containing proteins have been implicated in the regulation of the vacuolar/lysosomal membrane trafficking pathway and in regulation of signaling by TGFβ-receptors. 
Examples of Proteins: 
FYVE domain protein
Binding partner
EEA1(Early Endosome Antigen) PI(3)P
Hrs (Putative ATPase) PI(3)P
SARA (SMAD anchor for receptor activation PI(3)P



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