Allostery revealed within lipid binding events to membrane proteins

Membrane proteins interact with a myriad of lipid species in the biological membrane, leading to a bewildering number of possible protein−lipid assemblies. Despite this inherent complexity, the identification of specific protein−lipid interactions and the crucial role of lipids in the folding, structure, and function of membrane proteins is emerging from an increasing number of reports. Fundamental questions remain, however, regarding the ability of specific lipid binding events to membrane proteins to alter remote binding sites for lipids of a different type, a property referred to as allostery [Monod J, Wyman J, Changeux JP (1965)J Mol Biol12:88–118]. Here, we use native mass spectrometry to determine the allosteric nature of heterogeneous lipid binding events to membrane proteins. We monitored individual lipid binding events to the ammonia channel (AmtB) fromEscherichia coli, enabling determination of their equilibrium binding constants. We found that different lipid pairs display a range of allosteric modulation. In particular, the binding of phosphatidylethanolamine and cardiolipin-like molecules to AmtB exhibited the largest degree of allosteric modulation, inspiring us to determine the cocrystal structure of AmtB in this lipid environment. The 2.45-Å resolution structure reveals a cardiolipin-like molecule bound to each subunit of the trimeric complex. Mutation of a single residue in AmtB abolishes the positive allosteric modulation observed for binding phosphatidylethanolamine and cardiolipin-like molecules. Our results demonstrate that specific lipid−protein interactions can act as allosteric modulators for the binding of different lipid types to integral membrane proteins.

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Specific protein–lipid interactions in membrane proteins

Biochemical Society Transactions ◽

10.1042/bst0330938 ◽

2005 ◽

Vol 33 (5) ◽

pp. 938-942 ◽

Cited By ~ 56

Author(s):

C. Hunte

Keyword(s):

Membrane Proteins ◽

Membrane Protein ◽

Structural Integrity ◽

Protein Structures ◽

Specific Protein ◽

Lipid Binding ◽

Functional Roles ◽

Lipid Interactions ◽

Head Groups ◽

Lipid Species

Many membrane proteins selectively bind defined lipid species. This specificity has an impact on correct insertion, folding, structural integrity and full functionality of the protein. How are these different tasks achieved? Recent advances in structural research of membrane proteins provide new information about specific protein–lipid interactions. Tightly bound lipids in membrane protein structures are described and general principles of the binding interactions are deduced. Lipid binding is stabilized by multiple non-covalent interactions from protein residues to lipid head groups and hydrophobic tails. Distinct lipid-binding motifs have been identified for lipids with defined head groups in membrane protein structures. The stabilizing interactions differ between the electropositive and electronegative membrane sides. The importance of lipid binding for vertical positioning and tight integration of proteins in the membrane, for assembly and stabilization of oligomeric and multisubunit complexes, for supercomplexes, as well as for functional roles are pointed out.

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The energetics of protein–lipid interactions as viewed by molecular simulations

Biochemical Society Transactions ◽

10.1042/bst20190149 ◽

2019 ◽

Vol 48 (1) ◽

pp. 25-37 ◽

Cited By ~ 2

Author(s):

Robin A. Corey ◽

Phillip J. Stansfeld ◽

Mark S.P. Sansom

Keyword(s):

Membrane Proteins ◽

Biological Membrane ◽

Lipid Binding ◽

Integral Membrane Proteins ◽

Free Energies ◽

Computational Approaches ◽

Lipid Interactions ◽

Current State ◽

Peripheral Membrane Proteins ◽

Lipid Species

Membranes are formed from a bilayer containing diverse lipid species with which membrane proteins interact. Integral, membrane proteins are embedded in this bilayer, where they interact with lipids from their surroundings, whilst peripheral membrane proteins bind to lipids at the surface of membranes. Lipid interactions can influence the function of membrane proteins, either directly or allosterically. Both experimental (structural) and computational approaches can reveal lipid binding sites on membrane proteins. It is, therefore, important to understand the free energies of these interactions. This affords a more complete view of the engagement of a particular protein with the biological membrane surrounding it. Here, we describe many computational approaches currently in use for this purpose, including recent advances using both free energy and unbiased simulation methods. In particular, we focus on interactions of integral membrane proteins with cholesterol, and with anionic lipids such as phosphatidylinositol 4,5-bis-phosphate and cardiolipin. Peripheral membrane proteins are exemplified via interactions of PH domains with phosphoinositide-containing membranes. We summarise the current state of the field and provide an outlook on likely future directions of investigation.

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Faculty Opinions recommendation of Identification of specific lipid-binding sites in integral membrane proteins.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717948119.793453173 ◽

2012 ◽

Author(s):

Robert Vandenberg

Keyword(s):

Membrane Proteins ◽

Binding Sites ◽

Lipid Binding ◽

Integral Membrane Proteins ◽

Specific Lipid

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Novel Roles of SH2 and SH3 Domains in Lipid Binding

Cells ◽

10.3390/cells10051191 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1191

Author(s):

Szabolcs Sipeki ◽

Kitti Koprivanacz ◽

Tamás Takács ◽

Anita Kurilla ◽

Loretta László ◽

...

Keyword(s):

Protein Interactions ◽

Specific Protein ◽

Lipid Binding ◽

Sh2 Domain ◽

Essential Property ◽

Cellular Regulation ◽

Sh3 Domains ◽

Protein Partners ◽

Interaction Domains ◽

Central Paradigm

Signal transduction, the ability of cells to perceive information from the surroundings and alter behavior in response, is an essential property of life. Studies on tyrosine kinase action fundamentally changed our concept of cellular regulation. The induced assembly of subcellular hubs via the recognition of local protein or lipid modifications by modular protein interactions is now a central paradigm in signaling. Such molecular interactions are mediated by specific protein interaction domains. The first such domain identified was the SH2 domain, which was postulated to be a reader capable of finding and binding protein partners displaying phosphorylated tyrosine side chains. The SH3 domain was found to be involved in the formation of stable protein sub-complexes by constitutively attaching to proline-rich surfaces on its binding partners. The SH2 and SH3 domains have thus served as the prototypes for a diverse collection of interaction domains that recognize not only proteins but also lipids, nucleic acids, and small molecules. It has also been found that particular SH2 and SH3 domains themselves might also bind to and rely on lipids to modulate complex assembly. Some lipid-binding properties of SH2 and SH3 domains are reviewed here.

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Lipid-protein interactions are unique fingerprints for membrane proteins

10.1101/191486 ◽

2017 ◽

Author(s):

Valentina Corradi ◽

Eduardo Mendez-Villuendas ◽

Helgi I. Ingólfsson ◽

Ruo-Xu Gu ◽

Iwona Siuda ◽

...

Keyword(s):

Membrane Proteins ◽

Protein Interactions ◽

Cell Membranes ◽

Spatiotemporal Resolution ◽

Lipid Dynamics ◽

Lipid Species ◽

Lipid Environment ◽

Lipid Protein Interactions ◽

Dynamics Simulations ◽

Asymmetrically Distributed

ABSTRACTCell membranes contain hundreds of different proteins and lipids in an asymmetric arrangement. Understanding the lateral organization principles of these complex mixtures is essential for life and health. However, our current understanding of the detailed organization of cell membranes remains rather elusive, owing to the lack of experimental methods suitable for studying these fluctuating nanoscale assemblies of lipids and proteins with the required spatiotemporal resolution. Here, we use molecular dynamics simulations to characterize the lipid environment of ten membrane proteins. To provide a realistic lipid environment, the proteins are embedded in a model plasma membrane, where more than 60 lipid species are represented, asymmetrically distributed between leaflets. The simulations detail how each protein modulates its local lipid environment through local lipid composition, thickness, curvature and lipid dynamics. Our results provide a molecular glimpse of the complexity of lipid-protein interactions, with potentially far reaching implications for the overall organization of the cell membrane.

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Modulation of Function, Structure and Clustering of K+ Channels by Lipids: Lessons Learnt from KcsA

International Journal of Molecular Sciences ◽

10.3390/ijms21072554 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2554 ◽

Cited By ~ 3

Author(s):

María Lourdes Renart ◽

Ana Marcela Giudici ◽

Clara Díaz-García ◽

María Luisa Molina ◽

Andrés Morales ◽

...

Keyword(s):

Protein Interactions ◽

Experimental System ◽

Integral Membrane Protein ◽

Lipid Binding ◽

Common Element ◽

Protein Protein Interactions ◽

Expression And Purification ◽

Arginine Residues ◽

Channel Currents ◽

Specific Lipid

KcsA, a prokaryote tetrameric potassium channel, was the first ion channel ever to be structurally solved at high resolution. This, along with the ease of its expression and purification, made KcsA an experimental system of choice to study structure–function relationships in ion channels. In fact, much of our current understanding on how the different channel families operate arises from earlier KcsA information. Being an integral membrane protein, KcsA is also an excellent model to study how lipid–protein and protein–protein interactions within membranes, modulate its activity and structure. In regard to the later, a variety of equilibrium and non-equilibrium methods have been used in a truly multidisciplinary effort to study the effects of lipids on the KcsA channel. Remarkably, both experimental and “in silico” data point to the relevance of specific lipid binding to two key arginine residues. These residues are at non-annular lipid binding sites on the protein and act as a common element to trigger many of the lipid effects on this channel. Thus, processes as different as the inactivation of channel currents or the assembly of clusters from individual KcsA channels, depend upon such lipid binding.

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Molecular simulations and lipid–protein interactions: potassium channels and other membrane proteins

Biochemical Society Transactions ◽

10.1042/bst0330916 ◽

2005 ◽

Vol 33 (5) ◽

pp. 916-920 ◽

Cited By ~ 15

Author(s):

M.S.P. Sansom ◽

P.J. Bond ◽

S.S. Deol ◽

A. Grottesi ◽

S. Haider ◽

...

Keyword(s):

Membrane Proteins ◽

Binding Site ◽

Protein Interactions ◽

Outer Membrane Proteins ◽

Lipid Binding ◽

Potassium Channel Kcsa ◽

Head Groups ◽

Arginine Residues ◽

Lipid Protein Interactions ◽

Dynamics Simulations

Molecular dynamics simulations may be used to probe the interactions of membrane proteins with lipids and with detergents at atomic resolution. Examples of such simulations for ion channels and for bacterial outer membrane proteins are described. Comparison of simulations of KcsA (an α-helical bundle) and OmpA (a β-barrel) reveals the importance of two classes of side chains in stabilizing interactions with the head groups of lipid molecules: (i) tryptophan and tyrosine; and (ii) arginine and lysine. Arginine residues interacting with lipid phosphate groups play an important role in stabilizing the voltage-sensor domain of the KvAP channel within a bilayer. Simulations of the bacterial potassium channel KcsA reveal specific interactions of phosphatidylglycerol with an acidic lipid-binding site at the interface between adjacent protein monomers. A combination of molecular modelling and simulation reveals a potential phosphatidylinositol 4,5-bisphosphate-binding site on the surface of Kir6.2.

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Lipid–Protein Interactions in Plasma Membrane Organization and Function

Annual Review of Biophysics ◽

10.1146/annurev-biophys-090721-072718 ◽

2022 ◽

Vol 51 (1) ◽

Author(s):

Taras Sych ◽

Kandice R. Levental ◽

Erdinc Sezgin

Keyword(s):

Plasma Membrane ◽

Protein Interactions ◽

Collective Behavior ◽

Protein Function ◽

Lipid Binding ◽

Publication Date ◽

Membrane Organization ◽

Lipid Protein Interactions ◽

And Function ◽

Specific Lipid

Lipid–protein interactions in cells are involved in various biological processes, including metabolism, trafficking, signaling, host–pathogen interactions, and transmembrane transport. At the plasma membrane, lipid–protein interactions play major roles in membrane organization and function. Several membrane proteins have motifs for specific lipid binding, which modulate protein conformation and consequent function. In addition to such specific lipid–protein interactions, protein function can be regulated by the dynamic, collective behavior of lipids in membranes. Emerging analytical, biochemical, and computational technologies allow us to study the influence of specific lipid–protein interactions, as well as the collective behavior of membranes on protein function. In this article, we review the recent literature on lipid–protein interactions with a specific focus on the current state-of-the-art technologies that enable novel insights into these interactions. Expected final online publication date for the Annual Review of Biophysics, Volume 51 is May 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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