Ligand Binding Induces Conformational Changes in Human Cellular Retinol-binding Protein 1 (CRBP1) Revealed by Atomic Resolution Crystal Structures
Abstract
Important in regulating the uptake, storage, and metabolism of retinoids, cellular retinol-binding protein 1 (CRBP1) is essential for trafficking vitamin A through the cytoplasm. However, the molecular details of ligand uptake and targeted release by CRBP1 remain unclear. Here we report the first structure of CRBP1 in a ligand-free form as well as ultra-high resolution structures of this protein bound to either all-trans-retinol or retinylamine, the latter a therapeutic retinoid that prevents light-induced retinal degeneration. Superpositioning of human apo- and holo-CRBP1 revealed major differences within segments surrounding the entrance to the retinoid-binding site. These included α-helix II and hairpin turns between β-strands βC-βD and βE-βF as well as several side chains, such as Phe-57, Tyr-60, and Ile-77, that change their orientations to accommodate the ligand. Additionally, we mapped hydrogen bond networks inside the retinoid-binding cavity and demonstrated their significance for the ligand affinity. Analyses of the crystallographic B-factors indicated several regions with higher backbone mobility in the apoprotein that became more rigid upon retinoid binding. This conformational flexibility of human apo-CRBP1 facilitates interaction with the ligands, whereas the more rigid holoprotein structure protects the labile retinoid moiety during vitamin A transport. Furthermore, these findings suggest a mechanism of induced fitmore »
- Authors:
-
- Case Western Reserve Univ., Cleveland, OH (United States)
- Case Western Reserve Univ., Cleveland, OH (United States); Military Inst. of Medicine, Warsaw (Poland)
- Case Western Reserve Univ., Cleveland, OH (United States); Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH (United States)
- Cornell Univ., Ithaca, NY (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; USDOE Office of Science (SC), Biological and Environmental Research (BER); NIGMS; National Institutes of Health (NIH)
- OSTI Identifier:
- 1249223
- Grant/Contract Number:
- AC02-06CH11357; AC02-76SF00515; EY02394; P41GM103403; S10 RR029205; P41GM103393
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 291; Journal Issue: 16; Journal ID: ISSN 0021-9258
- Publisher:
- American Society for Biochemistry and Molecular Biology
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; lipid transport; retinal metabolism; retinoid-binding protein; retinol; vitamin A
Citation Formats
Silvaroli, Josie A., Arne, Jason M., Chelstowska, Sylwia, Kiser, Philip D., Banerjee, Surajit, and Golczak, Marcin. Ligand Binding Induces Conformational Changes in Human Cellular Retinol-binding Protein 1 (CRBP1) Revealed by Atomic Resolution Crystal Structures. United States: N. p., 2016.
Web. doi:10.1074/jbc.M116.714535.
Silvaroli, Josie A., Arne, Jason M., Chelstowska, Sylwia, Kiser, Philip D., Banerjee, Surajit, & Golczak, Marcin. Ligand Binding Induces Conformational Changes in Human Cellular Retinol-binding Protein 1 (CRBP1) Revealed by Atomic Resolution Crystal Structures. United States. https://doi.org/10.1074/jbc.M116.714535
Silvaroli, Josie A., Arne, Jason M., Chelstowska, Sylwia, Kiser, Philip D., Banerjee, Surajit, and Golczak, Marcin. Sun .
"Ligand Binding Induces Conformational Changes in Human Cellular Retinol-binding Protein 1 (CRBP1) Revealed by Atomic Resolution Crystal Structures". United States. https://doi.org/10.1074/jbc.M116.714535. https://www.osti.gov/servlets/purl/1249223.
@article{osti_1249223,
title = {Ligand Binding Induces Conformational Changes in Human Cellular Retinol-binding Protein 1 (CRBP1) Revealed by Atomic Resolution Crystal Structures},
author = {Silvaroli, Josie A. and Arne, Jason M. and Chelstowska, Sylwia and Kiser, Philip D. and Banerjee, Surajit and Golczak, Marcin},
abstractNote = {Important in regulating the uptake, storage, and metabolism of retinoids, cellular retinol-binding protein 1 (CRBP1) is essential for trafficking vitamin A through the cytoplasm. However, the molecular details of ligand uptake and targeted release by CRBP1 remain unclear. Here we report the first structure of CRBP1 in a ligand-free form as well as ultra-high resolution structures of this protein bound to either all-trans-retinol or retinylamine, the latter a therapeutic retinoid that prevents light-induced retinal degeneration. Superpositioning of human apo- and holo-CRBP1 revealed major differences within segments surrounding the entrance to the retinoid-binding site. These included α-helix II and hairpin turns between β-strands βC-βD and βE-βF as well as several side chains, such as Phe-57, Tyr-60, and Ile-77, that change their orientations to accommodate the ligand. Additionally, we mapped hydrogen bond networks inside the retinoid-binding cavity and demonstrated their significance for the ligand affinity. Analyses of the crystallographic B-factors indicated several regions with higher backbone mobility in the apoprotein that became more rigid upon retinoid binding. This conformational flexibility of human apo-CRBP1 facilitates interaction with the ligands, whereas the more rigid holoprotein structure protects the labile retinoid moiety during vitamin A transport. Furthermore, these findings suggest a mechanism of induced fit upon ligand binding by mammalian cellular retinol-binding proteins.},
doi = {10.1074/jbc.M116.714535},
journal = {Journal of Biological Chemistry},
number = 16,
volume = 291,
place = {United States},
year = {Sun Feb 21 00:00:00 EST 2016},
month = {Sun Feb 21 00:00:00 EST 2016}
}
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