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Special Issue "Modulation of Protein Structure and Function by Lipids"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 31 October 2023 | Viewed by 9341

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Dr. Avia Rosenhouse-Dantsker

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Guest Editor

Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA
Interests: structure–function relationship in proteins; protein–lipid interactions; lipid modulation of protein function; modulation of ion channel function; atrial and neuronal G protein-gated inwardly rectifying potassium channels; cholesterol; phosphoinositides; fatty acids

Special Issue Information

Dear Colleagues,

Since the introduction of the fluid mosaic model of cell membrane structure by Singer and Nicolson in 1972, our understanding of the roles of lipids in cellular functions has evolved significantly. Through insights gained with advances in technology, it has become clear that lipids are not merely passive entities that diffuse freely within membrane bilayers but are also key players in the modulation of protein function. Lipids, such as phosphoinositides, sterols, and fatty acids, have been shown to affect the function of a growing number of proteins (e.g., G protein-coupled receptors, ion channels, transporters, etc.). Lipids exert their effect on proteins through a variety of mechanisms, such as by modulating protein structure, function, and dynamics; promoting protein oligomerization; and mediating protein–protein interactions in the membrane. As a result, lipids have emerged as central players in diverse disease processes and, hence, in drug development, where lipid-regulated proteins are potential drug targets. The aim of this Special Issue is to provide an overview of the current understanding of the impact of lipids on protein structure and function in addition to presenting new developments in this field. Both original papers and reviews on this topic are welcome.

Dr. Avia Rosenhouse-Dantsker
Guest Editor

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Keywords

protein modulation by lipids
phosphoinositides
cholesterol
sterols
fatty acids
G protein-coupled receptors
ion channels
transporters

Published Papers (7 papers)

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Research

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Open AccessArticle

Cross-Linking Mass Spectrometry on P-Glycoprotein

Katalin F. Medzihradszky

and

Zsolt Bacso

Int. J. Mol. Sci. 2023, 24(13), 10627; https://doi.org/10.3390/ijms241310627 - 25 Jun 2023

Cited by 1 | Viewed by 991

Abstract

The ABC transporter P-glycoprotein (Pgp) has been found to be involved in multidrug resistance in tumor cells. Lipids and cholesterol have a pivotal role in Pgp’s conformations; however, it is often difficult to investigate it with conventional structural biology techniques. Here, we applied robust approaches coupled with cross-linking mass spectrometry (XL-MS), where the natural lipid environment remains quasi-intact. Two experimental approaches were carried out using different cross-linkers (i) on living cells, followed by membrane preparation and immunoprecipitation enrichment of Pgp, and (ii) on-bead, subsequent to membrane preparation and immunoprecipitation. Pgp-containing complexes were enriched employing extracellular monoclonal anti-Pgp antibodies on magnetic beads, followed by on-bead enzymatic digestion. The LC-MS/MS results revealed mono-links on Pgp’s solvent-accessible residues, while intraprotein cross-links confirmed a complex interplay between extracellular, transmembrane, and intracellular segments of the protein, of which several have been reported to be connected to cholesterol. Harnessing the MS results and those of molecular docking, we suggest an epitope for the 15D3 cholesterol-dependent mouse monoclonal antibody. Additionally, enriched neighbors of Pgp prove the strong connection of Pgp to the cytoskeleton and other cholesterol-regulated proteins. These findings suggest that XL-MS may be utilized for protein structure and network analyses in such convoluted systems as membrane proteins. Full article

(This article belongs to the Special Issue Modulation of Protein Structure and Function by Lipids)

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Open AccessArticle

Differential Functional Contribution of BK Channel Subunits to Aldosterone-Induced Channel Activation in Vascular Smooth Muscle and Eventual Cerebral Artery Dilation

and

Int. J. Mol. Sci. 2023, 24(10), 8704; https://doi.org/10.3390/ijms24108704 - 12 May 2023

Viewed by 857

Abstract

Calcium/voltage-activated potassium channels (BK) control smooth muscle (SM) tone and cerebral artery diameter. They include channel-forming α and regulatory β₁ subunits, the latter being highly expressed in SM. Both subunits participate in steroid-induced modification of BK activity: β₁ provides recognition for estradiol and cholanes, resulting in BK potentiation, whereas α suffices for BK inhibition by cholesterol or pregnenolone. Aldosterone can modify cerebral artery function independently of its effects outside the brain, yet BK involvement in aldosterone’s cerebrovascular action and identification of channel subunits, possibly involved in steroid action, remains uninvestigated. Using microscale thermophoresis, we demonstrated that each subunit type presents two recognition sites for aldosterone: at 0.3 and ≥10 µM for α and at 0.3–1 µM and ≥100 µM for β₁. Next, we probed aldosterone on SM BK activity and diameter of middle cerebral artery (MCA) isolated from β₁^−/− vs. wt mice. Data showed that β₁ leftward-shifted aldosterone-induced BK activation, rendering EC₅₀~3 μM and EC_MAX ≥ 10 μM, at which BK activity increased by 20%. At similar concentrations, aldosterone mildly yet significantly dilated MCA independently of circulating and endothelial factors. Lastly, aldosterone-induced MCA dilation was lost in β₁^−/− mice. Therefore, β₁ enables BK activation and MCA dilation by low µM aldosterone. Full article

(This article belongs to the Special Issue Modulation of Protein Structure and Function by Lipids)

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Open AccessArticle

Heart-Type Fatty Acid Binding Protein Binds Long-Chain Acylcarnitines and Protects against Lipotoxicity

Diana Zelencova-Gopejenko

Melita Videja

Aiga Grandane

Linda Pudnika-Okinčica

and

Int. J. Mol. Sci. 2023, 24(6), 5528; https://doi.org/10.3390/ijms24065528 - 14 Mar 2023

Viewed by 1093

Abstract

Heart-type fatty-acid binding protein (FABP3) is an essential cytosolic lipid transport protein found in cardiomyocytes. FABP3 binds fatty acids (FAs) reversibly and with high affinity. Acylcarnitines (ACs) are an esterified form of FAs that play an important role in cellular energy metabolism. However, an increased concentration of ACs can exert detrimental effects on cardiac mitochondria and lead to severe cardiac damage. In the present study, we evaluated the ability of FABP3 to bind long-chain ACs (LCACs) and protect cells from their harmful effects. We characterized the novel binding mechanism between FABP3 and LCACs by a cytotoxicity assay, nuclear magnetic resonance, and isothermal titration calorimetry. Our data demonstrate that FABP3 is capable of binding both FAs and LCACs as well as decreasing the cytotoxicity of LCACs. Our findings reveal that LCACs and FAs compete for the binding site of FABP3. Thus, the protective mechanism of FABP3 is found to be concentration dependent. Full article

(This article belongs to the Special Issue Modulation of Protein Structure and Function by Lipids)

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Open AccessArticle

Role of Thylakoid Lipids in Protochlorophyllide Oxidoreductase Activation: Allosteric Mechanism Elucidated by a Computational Study

and

Int. J. Mol. Sci. 2023, 24(1), 307; https://doi.org/10.3390/ijms24010307 - 24 Dec 2022

Viewed by 947

Abstract

Light-dependent protochlorophyllide oxidoreductase (LPOR) is a chlorophyll synthetase that catalyzes the reduction of protochlorophyllide (Pchlide) to chlorophyllide (Chlide) with indispensable roles in regulating photosynthesis processes. A recent study confirmed that thylakoid lipids (TL) were able to allosterically enhance modulator-induced LPOR activation. However, the allosteric modulation mechanism of LPOR by these compounds remains unclear. Herein, we integrated multiple computational approaches to explore the potential cavities in the Arabidopsis thaliana LPOR and an allosteric site around the helix-G region where high affinity for phosphatidyl glycerol (PG) was identified. Adopting accelerated molecular dynamics simulation for different LPOR states, we rigorously analyzed binary LPOR/PG and ternary LPOR/NADPH/PG complexes in terms of their dynamics, energetics, and attainable allosteric regulation. Our findings clarify the experimental observation of increased NADPH binding affinity for LPOR with PGs. Moreover, the simulations indicated that allosteric regulators targeting LPOR favor a mechanism involving lid opening upon binding to an allosteric hinge pocket mechanism. This understanding paves the way for designing novel LPOR activators and expanding the applications of LPOR. Full article

(This article belongs to the Special Issue Modulation of Protein Structure and Function by Lipids)

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Open AccessArticle

Bioinformatic Analysis of Na⁺, K⁺-ATPase Regulation through Phosphorylation of the Alpha-Subunit N-Terminus

and

Int. J. Mol. Sci. 2023, 24(1), 67; https://doi.org/10.3390/ijms24010067 - 21 Dec 2022

Cited by 2 | Viewed by 1128

Abstract

The Na⁺, K⁺-ATPase is an integral membrane protein which uses the energy of ATP hydrolysis to pump Na⁺ and K⁺ ions across the plasma membrane of all animal cells. It plays crucial roles in numerous physiological processes, such as cell volume regulation, nutrient reabsorption in the kidneys, nerve impulse transmission, and muscle contraction. Recent data suggest that it is regulated via an electrostatic switch mechanism involving the interaction of its lysine-rich N-terminus with the cytoplasmic surface of its surrounding lipid membrane, which can be modulated through the regulatory phosphorylation of the conserved serine and tyrosine residues on the protein’s N-terminal tail. Prior data indicate that the kinases responsible for phosphorylation belong to the protein kinase C (PKC) and Src kinase families. To provide indications of which particular enzyme of these families might be responsible, we analysed them for evidence of coevolution via the mirror tree method, utilising coevolution as a marker for a functional interaction. The results obtained showed that the most likely kinase isoforms to interact with the Na⁺, K⁺-ATPase were the θ and η isoforms of PKC and the Src kinase itself. These theoretical results will guide the direction of future experimental studies. Full article

(This article belongs to the Special Issue Modulation of Protein Structure and Function by Lipids)

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Open AccessArticle

Use of a Molecular Switch Probe to Activate or Inhibit GIRK1 Heteromers In Silico Reveals a Novel Gating Mechanism

and

Diomedes E. Logothetis

Int. J. Mol. Sci. 2022, 23(18), 10820; https://doi.org/10.3390/ijms231810820 - 16 Sep 2022

Cited by 3 | Viewed by 1108

Abstract

G protein-gated inwardly rectifying K⁺ (GIRK) channels form highly active heterotetramers in the body, such as in neurons (GIRK1/GIRK2 or GIRK1/2) and heart (GIRK1/GIRK4 or GIRK1/4). Based on three-dimensional atomic resolution structures for GIRK2 homotetramers, we built heterotetrameric GIRK1/2 and GIRK1/4 models in a lipid bilayer environment. By employing a urea-based activator ML297 and its molecular switch, the inhibitor GAT1587, we captured channel gating transitions and K⁺ ion permeation in sub-microsecond molecular dynamics (MD) simulations. This allowed us to monitor the dynamics of the two channel gates (one transmembrane and one cytosolic) as well as their control by the required phosphatidylinositol bis 4-5-phosphate (PIP₂). By comparing differences in the two trajectories, we identify three hydrophobic residues in the transmembrane domain 1 (TM1) of GIRK1, namely, F87, Y91, and W95, which form a hydrophobic wire induced by ML297 and de-induced by GAT1587 to orchestrate channel gating. This includes bending of the TM2 and alignment of a dipole of two acidic GIRK1 residues (E141 and D173) in the permeation pathway to facilitate K⁺ ion conduction. Moreover, the TM movements drive the movement of the Slide Helix relative to TM1 to adjust interactions of the CD-loop that controls the gating of the cytosolic gate. The simulations reveal that a key basic residue that coordinates PIP₂ to stabilize the pre-open and open states of the transmembrane gate flips in the inhibited state to form a direct salt-bridge interaction with the cytosolic gate and destabilize its open state. Full article

(This article belongs to the Special Issue Modulation of Protein Structure and Function by Lipids)

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Molecular Dynamics Simulations of Curved Lipid Membranes

Andreas Haahr Larsen

Int. J. Mol. Sci. 2022, 23(15), 8098; https://doi.org/10.3390/ijms23158098 - 22 Jul 2022

Cited by 4 | Viewed by 2210

Abstract

Eukaryotic cells contain membranes with various curvatures, from the near-plane plasma membrane to the highly curved membranes of organelles, vesicles, and membrane protrusions. These curvatures are generated and sustained by curvature-inducing proteins, peptides, and lipids, and describing these mechanisms is an important scientific challenge. In addition to that, some molecules can sense membrane curvature and thereby be trafficked to specific locations. The description of curvature sensing is another fundamental challenge. Curved lipid membranes and their interplay with membrane-associated proteins can be investigated with molecular dynamics (MD) simulations. Various methods for simulating curved membranes with MD are discussed here, including tools for setting up simulation of vesicles and methods for sustaining membrane curvature. The latter are divided into methods that exploit scaffolding virtual beads, methods that use curvature-inducing molecules, and methods applying virtual forces. The variety of simulation tools allow researcher to closely match the conditions of experimental studies of membrane curvatures. Full article

(This article belongs to the Special Issue Modulation of Protein Structure and Function by Lipids)

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