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Title: Ligand Binding Induces Conformational Changes in Human Cellular Retinol-binding Protein 1 (CRBP1) Revealed by Atomic Resolution Crystal Structures

Journal Article · · Journal of Biological Chemistry
 [1];  [1];  [2];  [3];  [4];  [1]
  1. Case Western Reserve Univ., Cleveland, OH (United States)
  2. Case Western Reserve Univ., Cleveland, OH (United States); Military Inst. of Medicine, Warsaw (Poland)
  3. Case Western Reserve Univ., Cleveland, OH (United States); Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH (United States)
  4. Cornell Univ., Ithaca, NY (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
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)
Grant/Contract Number:
AC02-06CH11357; AC02-76SF00515; EY02394; P41GM103403; S10 RR029205; P41GM103393
OSTI ID:
1249223
Journal Information:
Journal of Biological Chemistry, Vol. 291, Issue 16; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 35 works
Citation information provided by
Web of Science

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Porins and Amyloids are Coded by Similar Sequence Motifs journal November 2018
Molecular Basis for Vitamin A Uptake and Storage in Vertebrates journal October 2016

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
lipid transport
retinal metabolism
retinoid-binding protein
retinol
vitamin A