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J Mol Biol. 2001 Jan 26;305(4):939-49.

Localization of the RAR interaction domain of cellular retinoic acid binding protein-II.

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  • 1Division of Nutritional Sciences, Cornell Theory Center, Cornell University, Ithaca, NY 14853, USA.

Abstract

The pleiotropic effects of retinoic acid (RA) in mammalian cells are mediated by two classes of proteins: the retinoic acid receptors (RAR), and cellular retinoic acid binding proteins (CRABP-I and CRABP-II). The high conservation across species and the differential expression patterns of the two CRABPs suggest that they serve distinct biological functions. We previously showed that CRABP-II, but not CRABP-I, delivers RA to RAR through direct protein-protein interactions between the binding protein and the receptor. "Channeling" of RA between CRABP-II and RAR markedly facilitates the formation of the holo-receptor and, as a consequence, enhances the transcriptional activity of RAR in cells. Here, we localize the region of CRABP-II that mediates the interactions of this protein with RAR. Comparison between the electrostatic surface potential of CRABP-I and II revealed the presence of a sole region displaying a dramatic potential change between the two isoforms. Examination of the underlying model revealed that the change stemmed from CRABP-I/CRABP-II substitution of three spatially aligned residues E75Q, K81P, and E102 K, located on a protrusion above the entrance to the ligand binding pocket of the protein. Substituting the corresponding CRABP-II residues onto CRABP-I conferred upon this protein the ability to channel RA to RAR and to enhance the transcriptional activity of RAR in cells. Conversely, converting these amino acid residues in CRABP-II to the homologous CRABP-I residues resulted in loss of the ability of CRABP-II to interact with RAR and to augment the receptor's activity. The data demonstrate that the surface region of CRABP-II containing residues Gln75, Pro81, and Lys102 is necessary and sufficient for mediating the interactions of this protein with RAR, facilitating the formation of the holo-receptor, and enhancing the transcriptional activity of RA.

Copyright 2001 Academic Press.

PMID:
11162104
[PubMed - indexed for MEDLINE]
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