Vitamin A transport and the transmembrane pore in the cell-surface receptor for plasma retinol binding protein.
Vitamin A and its derivatives (retinoids) play diverse and crucial functions from embryogenesis to adulthood and are used as therapeutic agents in human medicine for eye and skin diseases, infections and cancer. Plasma retinol binding protein (RBP) is the principal and specific vitamin A carrier in the blood and binds vitamin A at 1:1 ratio. STRA6 is the high-affinity membrane receptor for RBP and mediates cellular vitamin A uptake. STRA6 null mice have severely depleted vitamin A reserves for vision and consequently have vision loss, even under vitamin A sufficient conditions. STRA6 null humans have a wide range of severe pathological phenotypes in many organs including the eye, brain, heart and lung. Known membrane transport mechanisms involve transmembrane pores that regulate the transport of the substrate (e.g., the gating of ion channels). STRA6 represents a new type of membrane receptor. How this receptor interacts with its transport substrate vitamin A and the functions of its nine transmembrane domains are still completely unknown. These questions are critical to understanding the molecular basis of STRA6's activities and its regulation. We employ acute chemical modification to introduce chemical side chains to STRA6 in a site-specific manner. We found that modifications with specific chemicals at specific positions in or near the transmembrane domains of this receptor can almost completely suppress its vitamin A transport activity. These experiments provide the first evidence for the existence of a transmembrane pore, analogous to the pore of ion channels, for this new type of cell-surface receptor.
Department of Physiology, Jules Stein Eye Institute, and Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.
Ming
M
Zhong
Riki
R
Kawaguchi
Mariam
M
Ter-Stepanian
Miki
M
Kassai
Hui
H
Sun
D019943:Amino Acid Substitution; D000818:Animals; D001692:Biological Transport; D001710:Biotin / Q000031:analogs & derivatives / Q000737:chemistry; D019556:COS Cells; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D017433:Protein Structure, Secondary; D054840:Retinol-Binding Proteins, Cellular / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism*
D008565:Membrane Proteins; C419543:N-biotinylaminoethyl methanethiosulfonate; D054840:Retinol-Binding Proteins, Cellular; C519685:STRA6 protein, human; D014801:Vitamin A; D001710:Biotin