Interactions amongst plasma retinol-binding protein, transthyretin and their ligands: implications in vitamin A homeostasis and transthyretin amyloidosis.

Retinol transport complex consisting of retinol-binding protein (RBP) and transthyretin (TTR) is involved in the transport of retinol (vitamin A) and thyroxine (T(4)) in the human plasma. RBP is a 21-kDa single polypeptide chain protein, synthesized in the liver, which binds and transports retinol to the target organs. The circulating RBP binds to another protein called TTR, a 55-kDa homotetrameric T(4) transport protein. Such protein-protein complex formation is thought to prevent glomerular filtration of low molecular mass RBP. Misfolding and aggregation of TTR is implicated in amyloid disorders such as familial amyloid polyneuropathy (FAP) and senile systemic amyloidosis (SSA). Recent observations suggest that both RBP and T(4), the physiological ligands of TTR, prevent its misfolding and amyloid fibril formation, suggesting yet another structure-function relationship to this protein-protein complex. TTR2, a poorly characterized protein, was also found bound to RBP in human and pig plasma but its significance remains to be understood. Furthermore, knockout models of both RBP and TTR unequivocally demonstrated the importance of this protein-protein complex in retinoid transport. Thus, interactions amongst multiple components of retinol transport play critical roles in vitamin A homeostasis and TTR amyloidosis.