FYVE domains are highly conserved
protein modules that typically bind
phosphatidylinositol 3-phosphate (PI3P) on the surface of early endosomes. Along with
pleckstrin homology (PH) and
phox homology (PX) domains, FYVE domains are the principal readers of the
phosphoinositide (PI) code that mediate specific recognition of eukaryotic organelles. Of all the human FYVE domain containing
proteins, those within the
faciogenital dysplasia (Fgd) subfamily are particularly divergent and couple with
GTPases to exert unique cellular functions. The subcellular distributions and functions of these evolutionarily conserved signal transducers, which also include Dbl homology (DH) and two PH domains, are discussed here to better understand the
biological range of processes that such multidomain
proteins engage in. Determinants of their various functions include specific multidomain architectures, posttranslational modifications including PIP stops that have been discovered in
sorting nexins, PI recognition motifs, and
phospholipid-binding surfaces as defined by the Membrane Optimal Docking Area (MODA) program. How these orchestrate Fgd function remains unclear but has implications for developmental diseases including
Aarskog-Scott syndrome, which is also known as
faciogenital dysplasia, and forms of
cancer that are associated with mutations and amplifications of Fgd genes.