Retinoid binding to retinol-binding protein and the interference with the interaction with transthyretin.
The retinol carrier retinol-binding protein (RBP) forms a complex with the thyroid hormone binding protein transthyretin in the plasma of a number of vertebrate species. The interactions of retinoid-RBP complexes, as well as of unliganded RBP, with transthyretin have been investigated by means of fluorescence anisotropy studies. The presence of two independent and equivalent RBP binding sites per transthyretin molecule has been established for proteins purified from species distant in evolution. Although the natural ligand retinol participates in the interaction between retinol-RBP and transthyretin, its binding to RBP is not a prerequisite for protein-protein interaction. The dissociation constants of human transthyretin binding liganded and unliganded forms of human RBP were determined to be: all-trans retinol-RBP, Kd approximately 0.2 microM; apoRBP, Kd approximately 1.2 microM; all-trans retinoic acid-RBP, Kd approximately 0.8 microM; all-trans retinyl methyl ether-RBP, Kd approximately 6 microM. The complex of RBP with the synthetic retinoid fenretinide, which bears the bulky hydroxyphenyl end group, exhibits negligible affinity for transthyretin. The replacement of RBP-bound retinol with synthetic retinoids affects RBP-transthyretin recognition to an extent that appears to be well correlated with the nature and steric hindrance of the groups substituting the retinol hydroxyl group, consistent with their location at the interface between the contact areas of RBP and transthyretin.
Malpeli
G
G
Institute of Biochemical Sciences, Science Faculty, University of Parma, Italy.
Folli
C
C
Berni
R
R
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D001059:Apoproteins / Q000378:metabolism; D002645:Chickens; D003619:Dansyl Compounds / Q000378:metabolism; D017313:Fenretinide / Q000494:pharmacology; D005454:Fluorescence Polarization; D006801:Humans; D015394:Molecular Structure; D011228:Prealbumin / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D012176:Retinoids / Q000378:metabolism / Q000494:pharmacology*; D012177:Retinol-Binding Proteins / Q000378:metabolism*; D054839:Retinol-Binding Proteins, Plasma; D013974:Thyroxine / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism; D014801:Vitamin A / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
D000970:Antineoplastic Agents; D001059:Apoproteins; D003619:Dansyl Compounds; D011228:Prealbumin; C101326:RBP4 protein, human; D012176:Retinoids; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D014801:Vitamin A; D017313:Fenretinide; C022613:retinyl methyl ether; D014212:Tretinoin; D013974:Thyroxine; C029038:dansyl chloride