The StAR-related lipid transfer (START) domain is a protein module of approximately 210 amino acids that binds a variety of lipids, including sterols . The START domain is conserved through evolution in plants and animals and serves as a versatile binding interface for lipids that function in many distinct processes . In humans, the START domain is found in 15 distinct proteins, either alone or associated with other protein domains .
StAR-related lipid transfer domain containing 5 (STARD5) is a protein encoded by the STARD5 gene in humans . The protein is 213 amino acids long and consists almost entirely of a START domain . STARD5 is part of the StarD4 subfamily of START domain proteins, sharing 34% sequence identity with STARD4 .
STARD5 binds both cholesterol and 25-hydroxycholesterol and appears to function to redistribute cholesterol to the endoplasmic reticulum and/or the plasma membrane . The protein is most prevalent in the kidney and liver, where it is found in Kupffer cells . Increased levels of STARD5 increase free cholesterol in the cell .
Cholesterol homeostasis is regulated, at least in part, by sterol regulatory element-binding proteins (SREBPs) and liver X receptors (LXRs) . Upon sterol depletion, LXRs are inactive, and SREBPs are cleaved, after which they bind promoter SREs and activate genes involved in cholesterol biosynthesis and uptake . Sterol transport is mediated by vesicles or by soluble protein carriers, such as steroidogenic acute regulatory protein (STAR) .
The crystal structures of several START domain proteins have been solved, revealing a conserved helix-grip
fold that forms an inner tunnel wide enough to accommodate the hydrophobic lipid . The C-terminal end of the domain plays a fundamental role, forming a lid over a deep lipid-binding pocket that shields the ligand from the external environment .
Mammalian START proteins have diverse expression patterns and can be found free in the cytoplasm, attached to membranes, or in the nucleus . They appear to function in various physiological processes, such as lipid transfer between intracellular compartments, lipid metabolism, and modulation of signaling events . Mutation or misexpression of START proteins is linked to pathological processes, including genetic disorders, autoimmune diseases, and cancer .