Structure and function of the enigmatic Sec 14 domain-containing proteins and the etiology of human disease

Proteins containing the Sec14 domain, also referred to as the CRAL-TRIO domain, are found throughout Eukarya. Sec 14 domains bind a single lipophilic molecule with the hydrophobic tail oriented toward the middle of the protein and the hydrophilic head group oriented outward. There are 29 human genes that contain this domain, while the Saccharomyces cerevisiae genome encodes six. In humans, the Sec 14 domain is often embedded as part of a larger protein, many of which are GEFs and GAPs, implying that regulation of small G proteins may be a functional theme that unites many Sec14 domain-containing proteins. Although evidence supports a role for Sec14 domains in integrating the metabolism of their specific lipophilic ligand with cell functions, the precise mechanisms are poorly understood. Delineating how ligand binding by Sec14 domains translates into alterations in the function of proteins in which they are contained is particularly important. Mutations in several human Sec14 domain-containing proteins result in the onset of human diseases that include cancer, blindness and neurodegeneration.