New insights on the protein-ligand interaction differences between the two primary cellular retinol carriers

Franzoni, L.; Cavazzini, D.; Rossi, Gian Luigi; Lücke, Christian

doi:10.1194/jlr.m002006

Cited by 11 publications

(13 citation statements)

References 52 publications

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“…37 Our results are consistent with conclusions from previous NMR relaxation and NOE measurements on bovine heart FABP and porcine ILBP. 42 Both proteins belong to the iLBP family, but in bovine heart FABP strands 4 and 5 are stabilized by a cross-strand aromatic pair (F64-F70) while in porcine ILBP the pair is absent.…”

Section: Discussionsupporting

confidence: 92%

“…Phe ladders similar to the one present in CRABP1 22 have been found in several iLBP family members, e.g. intestinal fatty-acid binding protein (IFABP) 36 and cellular retinol-binding proteins (CRBPs) 1 and 2 37 . To assess how conserved this ladder is in other iLBPs we performed a systematic search on the level of primary and tertiary structures.…”

Section: Resultsmentioning

confidence: 80%

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The Role of Aromatic–Aromatic Interactions in Strand–Strand Stabilization of β-Sheets

Budyak¹,

Zhuravleva²,

Gierasch³

2013

Journal of Molecular Biology

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Aromatic-aromatic interactions have long been believed to play key roles in protein structure, folding, and binding functions. Yet we still lack full understanding of the contributions of aromatic-aromatic interactions to protein stability and the timing of their formation during folding. Here, using as a case study an aromatic ladder in the β-barrel protein, cellular retinoic acid binding protein 1 (CRABP1), we find aromatic π stacking plays a greater role in the Phe65-Phe71 cross-strand pair while in another pair, Phe50-Phe65, hydrophobic interactions are dominant. The Phe65/Phe71 pair spans β-strands 4 and 5 in the β-barrel, which lack interstrand hydrogen bonding, and we speculate that it compensates energetically for the absence of strand-strand backbone interactions. Using perturbation analysis, we find that both aromatic-aromatic pairs form after the transition state for folding of CRABP1, thus playing a role in the final stabilization of the β-sheet rather than in its nucleation as had been earlier proposed. The aromatic interaction between strands 4–5 in CRABP1 is highly conserved in the intracellular lipid-binding protein (iLBP) family, and several lines of evidence combine to support a model wherein it acts to maintain barrel structure while allowing the dynamic opening that is necessary for ligand entry. Lastly, we carried out a bioinformatic analysis and found 51 examples of aromatic-aromatic interactions across non-hydrogen-bonded β-strands outside the iLBPs, arguing for the generality of the role played by this structural motif.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 80%

The Role of Aromatic–Aromatic Interactions in Strand–Strand Stabilization of β-Sheets

Budyak¹,

Zhuravleva²,

Gierasch³

2013

Journal of Molecular Biology

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“…Data generated since the first X-ray crystallography and the proteolysis and mutagenesis experiments support the results and deductions of these early studies, concerning differences in structure between apo and holo CRBP1, a conformation change upon ligand binding, the contribution of the helix-turn-helix and other portal residues to the conformation change and/or to ligand binding, and ligand egress relying on “external” partners, rather than by diffusion (Li et al, 1991; Franzoni et al, 2002; Lu et al, 2003; Careri et al, 2006; Mittag et al, 2006; Franzoni et al, 2010; Silvaroli et al, 2016). These studies have refined and added additional detailed insight into the nature of the apo- and holo-CRBP1 structures.…”

Section: Structures Of Retinoid Binding-proteinsmentioning

confidence: 72%

“…a) Ribbon diagram of CRBP1 illustrating the entrance portal, key residues, orientation of retinol in the binding pocket, and the structure of the β-clam (Cowan et al, 1993; Franzoni et al, 2002; Lu et al, 2003; Careri et al, 2006; Mittag et al, 2006; Franzoni et al, 2010; 2016 Silvaroli et al, 2016). Red shows the hydroxyl group of retinol.…”

Section: Figmentioning

confidence: 99%

Cellular retinoid binding-proteins, CRBP, CRABP, FABP5: Effects on retinoid metabolism, function and related diseases

Napoli

2017

Pharmacology & Therapeutics

202

180

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Cellular binding-proteins (BP), including CRBP1, CRBP2, CRABP1, CRABP2, and FABP5, shepherd the poorly aqueous soluble retinoids during uptake, metabolism and function. Holo-BP promote efficient use of retinol, a scarce but essential nutrient throughout evolution, by sheltering it and its major metabolite all-trans-retinoic acid from adventitious interactions with the cellular milieu, and by imposing specificity of delivery to enzymes, nuclear receptors and other partners. Apo-BP reflect cellular retinoid status and modify activities of retinoid metabolon enzymes, or exert non-canonical actions. High ligand binding affinities and the nature of ligand sequestration necessitate external factors to prompt retinoid release from holo-BP. One or more of cross-linking, kinetics, and colocalization have identified these factors as RDH, RALDH, CYP26, LRAT, RAR and PPARβ/δ. Michaelis-Menten and other kinetic approaches verify that BP channel retinoids to select enzymes and receptors by protein-protein interactions. Function of the BP and enzymes that constitute the retinoid metabolon depends in part on retinoid exchanges unique to specific pairings. The complexity of these exchanges configure retinol metabolism to meet the diverse functions of all-trans-retinoic acid and its ability to foster contrary outcomes in different cell types, such as inducing apoptosis, differentiation or proliferation. Altered BP expression affects retinoid function, for example, by impairing pancreas development resulting in abnormal glucose and energy metabolism, promoting predisposition to breast cancer, and fostering more severe outcomes in prostate cancer, ovarian adenocarcinoma, and glioblastoma. Yet, the extent of BP interactions with retinoid metabolon enzymes and their impact on retinoid physiology remains incompletely understood.

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“…This difference was confirmed by limited proteolysis, which demonstrated resistance of holo-CRBP1 to multiple proteases, whereas apo-CRBP1 was digested by the endopeptidase Arg-C at R30 in α-helix II [100, 175]. Since the determination of the structure by X-ray, several NMR studies and a mass spectrometry-based study have confirmed and expanded insight into the flexibility and the ligand entry portal [38, 72, 73, 134, 135, 144, 158]. CRBP1 has a flattened β-barrel (aka β-clam) shape formed by two orthogonal β-sheets (Fig.…”

Section: Current State Of the Fieldmentioning

confidence: 99%

Functions of Intracellular Retinoid Binding-Proteins

Napoli

2016

Subcellular Biochemistry

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Multiple binding and transport proteins facilitate many aspects of retinoid biology through effects on retinoid transport, cellular uptake, metabolism, and nuclear delivery. These include the serum retinol binding protein sRBP (aka Rbp4), the plasma membrane sRBP receptor Stra6, and the intracellular retinoid binding-proteins such as cellular retinol-binding proteins (CRBP) and cellular retinoic acid binding-proteins (CRABP). sRBP transports the highly lipophilic retinol through an aqueous medium. The major intracellular retinol-binding protein, CRBP1, likely enhances efficient retinoid use by providing a sink to facilitate retinol uptake from sRBP through the plasma membrane or via Stra6, delivering retinol or retinal to select enzymes that generate retinyl esters or retinoic acid, and protecting retinol/retinal from excess catabolism or opportunistic metabolism. Intracellular retinoic acid binding-proteins (CRABP1 and 2, and FABP5) seem to have more diverse functions distinctive to each, such as directing retinoic acid to catabolism, delivering retinoic acid to specific nuclear receptors, and generating non-canonical actions. Gene ablation of intracellular retinoid binding-proteins does not cause embryonic lethality or gross morphological defects. Metabolic and functional defects manifested in knockouts of CRBP1, CRBP2 and CRBP3, however, illustrate their essentiality to health, and in the case of CRBP2, to survival during limited dietary vitamin A. Future studies should continue to address the specific molecular interactions that occur between retinoid binding-proteins and their targets and their precise physiologic contributions to retinoid homeostasis and function.

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New insights on the protein-ligand interaction differences between the two primary cellular retinol carriers

Cited by 11 publications

References 52 publications

The Role of Aromatic–Aromatic Interactions in Strand–Strand Stabilization of β-Sheets

The Role of Aromatic–Aromatic Interactions in Strand–Strand Stabilization of β-Sheets

Cellular retinoid binding-proteins, CRBP, CRABP, FABP5: Effects on retinoid metabolism, function and related diseases

Functions of Intracellular Retinoid Binding-Proteins

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