Transthyretin – Retinol-binding protein 4 interface (TTR-RBP4 interface)

The Transthyretin – Retinol-binding protein 4 (TTR-RBP4) interface is a critical protein-protein interaction site responsible for the transport of Vitamin A (retinol) in the blood (UniProt P02766, P02753). Under physiological conditions, RBP4 binds to retinol and subsequently forms a complex with the tetrameric protein TTR, which increases the molecular weight of the complex to prevent the small RBP4 molecule from being filtered and excreted by the kidneys (PubMed: 25135597). In certain ocular diseases, such as Stargardt disease and dry age-related macular degeneration, the accumulation of retinol-derived toxic byproducts like A2E in the retinal pigment epithelium leads to progressive vision loss (PubMed: 31433144). Therapeutic strategies targeting this interface involve small molecules, such as Tinlarebant, that bind to RBP4 and induce a conformational change or steric hindrance that prevents its association with TTR (Belite Bio). This disruption results in the rapid renal clearance of RBP4 and a subsequent reduction in circulating retinol levels, thereby limiting the 'fuel' available for the formation of toxic bisretinoids in the eye.

Other names

TTR-RBP4 complexTransthyretin-Retinol binding protein 4 interaction siteRBP4-TTR interface

Disruption of the protein-protein interaction between Transthyretin and Retinol-binding protein 4 to promote renal clearance of RBP4 and reduce systemic retinol levels.