Abstract
A crystal structure of the lutein-binding domain of human StARD3 (StAR-related lipid-transfer protein 3; also known as MLN64) has been refined to 1.74 Å resolution. A previous structure of the same protein determined to 2.2 Å resolution highlighted homology with StARD1 and shared cholesterol-binding character. StARD3 has since been recognized as a carotenoid-binding protein in the primate retina, where its biochemical function of binding lutein with specificity appears to be well suited to recruit this photoprotective molecule. The current and previous structures correspond closely to each other (r.m.s.d. of 0.25 Å), especially in terms of the helix-grip fold constructed around a solvent-filled cavity. Regions of interest were defined with alternate conformations in the current higher-resolution structure, including Arg351 found within the cavity and Ω1, a loop of four residues found just outside the cavity entrance. Models of the complex with lutein generated by rigid-body docking indicate that one of the ionone rings must protrude outside the cavity, and this insight has implications for molecular interactions with transport proteins and enzymes that act on lutein. Interestingly, models with the ℇ-ionone ring characteristic of lutein pointing towards the bottom of the cavity were associated with fewer steric clashes, suggesting that steric complementarity and ligand asymmetry may play a role in discriminating lutein from the other ocular carotenoids zeaxanthin and meso-zeaxanthin, which only have β-ionone rings.
Highlights
The macula lutea at the center of the primate retina is enriched in the xanthophyll carotenoids lutein, zeaxanthin and meso-zeaxanthin
Its retina-related role was confirmed through the examination of tissue-specific expression patterns, and binding studies monitored by surface plasmon resonance (SPR) demonstrated that StARD3 binds lutein with affinity and specificity (Li et al, 2011)
We suggest that the salt bridge found in cavities of StARD3 and StARD1 may act as an allosteric trigger point to communicate ligand binding to other components of the steroid-generating apparatus in the case of StARD1, and to retinal proteins and enzymes involved with xanthophyll transport and metabolism in the case of StARD3
Summary
The macula lutea (yellow spot) at the center of the primate retina is enriched in the xanthophyll carotenoids lutein, zeaxanthin and meso-zeaxanthin. Epidemiological studies and prospective clinical trials have shown that dietary intake and supplementation with lutein and zeaxanthin increase the likelihood of avoiding age-related macular degeneration (AMD), a leading cause of blindness (Seddon et al, 1994; Age-Related Eye Disease Study 2 Research Group, 2014; Wu et al, 2015; Bernstein et al, 2016). The majority of these carotenoid molecules are localized in the outer plexiform layers ( known as the Henle fiber layer) of the human fovea. The luteinbinding function of StARD3 resides within the C-terminal START domain comprising residues 216–444, hereafter referred to as StARD3LBD (Li et al, 2011)
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