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Ligand Interactions and Conformational Dynamics of Cellular Retinol-Binding Proteins: Implications for Ocular and Intestinal Health /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Ligand Interactions and Conformational Dynamics of Cellular Retinol-Binding Proteins: Implications for Ocular and Intestinal Health // Jacqueline Plau.
Author:	Plau, Jacqueline,
Description:	1 electronic resource (220 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-04, Section: B.
Contained By:	Dissertations Abstracts International86-04B.
Subject:	Pharmacology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31649327
ISBN:	9798384067528

Ligand Interactions and Conformational Dynamics of Cellular Retinol-Binding Proteins: Implications for Ocular and Intestinal Health /
Plau, Jacqueline,

Ligand Interactions and Conformational Dynamics of Cellular Retinol-Binding Proteins: Implications for Ocular and Intestinal Health /Jacqueline Plau. - 1 electronic resource (220 pages)

Source: Dissertations Abstracts International, Volume: 86-04, Section: B.

Retinol‐binding proteins play a pivotal role for the regulation of the retinoid metabolism, thereby influencing crucial physiological processes such as vision, cell division, organogenesis, and immunity. Dysregulation of retinoid metabolism can lead to a variety of pathologies, ranging from retinal diseases to unfavorable metabolic changes. Studying the interactions of retinol‐binding proteins with their ligands not only enhances our understanding of retinoid metabolism regulation, but also presents opportunities for therapeutic intervention. This study centers on two cellular retinol‐binding proteins (CRBPs), namely CRBP1 and CRBP2. CRBP1 is being explored in the context of therapeutic application in specific ocular diseases, while CRBP2s's investigation centers on its newly found role as a binding protein of monoacylglycerol (MAGs) and N‐acylethanolamine. This investigation establishes relationships between non‐retinoid compounds and their interaction with CRBPs, revealing the interplay between ligand affinity, specificity, and protein dynamics.In the context of prevalent ocular diseases such as age‐related macular degeneration and Stargardt disease, a potential target for beneficially altering the ocular retinoid metabolism is CRBP1, the main transporter for all‐trans‐retinol in the eye. Inhibition of CRBP1 has been shown to protect mouse retinas from light‐induced photoreceptor damage. In search for competitive non‐retinoid inhibitors of CRBP1, a high‐throughput screening was conducted. Using X‐ray crystallography, hydrogen‐deuterium exchange mass spectrometry, and molecular dynamics simulations, we studied the interaction mechanisms and conformational changes of CRBP1 with the newly discovered inhibitors. These studies provide evidence for the functional significance of the "closed" conformation of CRBP1 and established the molecular foundation for understanding high‐affinity interactions of non‐retinoid ligands with this protein. To validate CRBP1 as a therapeutic target, CRBP1 deficient (Rbp1‐/‐ ) mice were crossed with Abca4‐/‐ Rdh8‐/‐ mice, which functions as a model for Stargardt disease, displaying irreversible accumulation of bisretinoids, specifically pyridinium bisretinoid (A2E). The resulting triple knockout mice Abca4‐/‐ Rdh8‐/‐ Rbp1‐/‐ mice displayed significantly less A2E accumulation than Abca4‐/‐ Rdh8‐/‐ mice, providing a genetic validation of CRBP1 as a therapeutic target for the pharmacological treatment of retinal degenerative diseases.Although CRBP2 is known to be the main facilitator of dietary retinoid uptake and transport in the small intestine, recent findings indicate it also interacts with non‐ retinoids such as MAGs and, lipid signaling molecules, such as 2‐arachidonoylglycerol. To investigate the role of CRBP2 in the metabolism of MAGs, a high‐throughput screen was performed to map the interactome for this lipid‐binding protein. The results provide evidence for the selective interaction of CRBP2 with a subset of endogenous non‐retinoid ligands with its highest affinity for sn‐1 and sn‐2 MAGs that contain polyunsaturated C18‐C20 acyl chains. Additionally, the structure‐affinity relationship for selected lipids was thoroughly investigated. Further elucidation of the molecular basis for the binding specificity was provided by analyzing high‐resolution crystal structures of CRBP2 in complex with derivatives of MAGs. Finally, T51 and V62 were identified as key amino acids in CRBP2 that enable the broadening of ligand selectivity to MAGs, contrary to CRBP1. Thus, this study provides the molecular framework for understanding the lipid selectivity and diverse functions of CRBPs in controlling lipid homeostasis.Overall, this investigation sheds light on the structure and binding relationships of CRBPs through the in‐depth analysis of CRBP1 and CRBP2 bound non‐retinoids and discusses implications for retinoid homeostasis and lipid metabolism.

English

ISBN: 9798384067528Subjects--Topical Terms:

634543
Pharmacology.
Subjects--Index Terms:

Immunity

Ligand Interactions and Conformational Dynamics of Cellular Retinol-Binding Proteins: Implications for Ocular and Intestinal Health /
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520 $a Retinol‐binding proteins play a pivotal role for the regulation of the retinoid metabolism, thereby influencing crucial physiological processes such as vision, cell division, organogenesis, and immunity. Dysregulation of retinoid metabolism can lead to a variety of pathologies, ranging from retinal diseases to unfavorable metabolic changes. Studying the interactions of retinol‐binding proteins with their ligands not only enhances our understanding of retinoid metabolism regulation, but also presents opportunities for therapeutic intervention. This study centers on two cellular retinol‐binding proteins (CRBPs), namely CRBP1 and CRBP2. CRBP1 is being explored in the context of therapeutic application in specific ocular diseases, while CRBP2s's investigation centers on its newly found role as a binding protein of monoacylglycerol (MAGs) and N‐acylethanolamine. This investigation establishes relationships between non‐retinoid compounds and their interaction with CRBPs, revealing the interplay between ligand affinity, specificity, and protein dynamics.In the context of prevalent ocular diseases such as age‐related macular degeneration and Stargardt disease, a potential target for beneficially altering the ocular retinoid metabolism is CRBP1, the main transporter for all‐trans‐retinol in the eye. Inhibition of CRBP1 has been shown to protect mouse retinas from light‐induced photoreceptor damage. In search for competitive non‐retinoid inhibitors of CRBP1, a high‐throughput screening was conducted. Using X‐ray crystallography, hydrogen‐deuterium exchange mass spectrometry, and molecular dynamics simulations, we studied the interaction mechanisms and conformational changes of CRBP1 with the newly discovered inhibitors. These studies provide evidence for the functional significance of the "closed" conformation of CRBP1 and established the molecular foundation for understanding high‐affinity interactions of non‐retinoid ligands with this protein. To validate CRBP1 as a therapeutic target, CRBP1 deficient (Rbp1‐/‐ ) mice were crossed with Abca4‐/‐ Rdh8‐/‐ mice, which functions as a model for Stargardt disease, displaying irreversible accumulation of bisretinoids, specifically pyridinium bisretinoid (A2E). The resulting triple knockout mice Abca4‐/‐ Rdh8‐/‐ Rbp1‐/‐ mice displayed significantly less A2E accumulation than Abca4‐/‐ Rdh8‐/‐ mice, providing a genetic validation of CRBP1 as a therapeutic target for the pharmacological treatment of retinal degenerative diseases.Although CRBP2 is known to be the main facilitator of dietary retinoid uptake and transport in the small intestine, recent findings indicate it also interacts with non‐ retinoids such as MAGs and, lipid signaling molecules, such as 2‐arachidonoylglycerol. To investigate the role of CRBP2 in the metabolism of MAGs, a high‐throughput screen was performed to map the interactome for this lipid‐binding protein. The results provide evidence for the selective interaction of CRBP2 with a subset of endogenous non‐retinoid ligands with its highest affinity for sn‐1 and sn‐2 MAGs that contain polyunsaturated C18‐C20 acyl chains. Additionally, the structure‐affinity relationship for selected lipids was thoroughly investigated. Further elucidation of the molecular basis for the binding specificity was provided by analyzing high‐resolution crystal structures of CRBP2 in complex with derivatives of MAGs. Finally, T51 and V62 were identified as key amino acids in CRBP2 that enable the broadening of ligand selectivity to MAGs, contrary to CRBP1. Thus, this study provides the molecular framework for understanding the lipid selectivity and diverse functions of CRBPs in controlling lipid homeostasis.Overall, this investigation sheds light on the structure and binding relationships of CRBPs through the in‐depth analysis of CRBP1 and CRBP2 bound non‐retinoids and discusses implications for retinoid homeostasis and lipid metabolism.
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