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8.D.4.  The Nanodisc (ND) Family 

The advent of amphiphilic copolymers enables integral membrane proteins to be solubilized into stable 10-30 nm native nanodiscs to resolve their multisubunit structures, post-translational modifications, endogenous lipid bilayers, and small molecule ligands (Brown et al. 2021). This has positioned biological membrane:protein assemblies (memteins) as fundamental functional units of cellular membranes. Brown et al. 2021 reviewed copolymer design strategies and methods for the characterization of transmembrane proteins within native nanodiscs by cryo-electron microscopy (cryo-EM), transmission electron microscopy (TEM), nuclear magnetic resonance (NMR) spectroscopy, electron paramagnetic resonance (EPR), X-ray diffraction, surface plasmon resonance (SPR), and mass spectrometry (MS). Nanodiscs consist of a patch of a planar lipid bilayer that is encircled by different biopolymers to form particles of defined and tunable size. Klöpfer and Hagn 2019 provided an overview of available membrane mimetics, including nanodiscs, amphipols (TC# 8.D.1) and bicelles (TC#8.A.5), that are suitable for high-resolution NMR spectroscopy. They described how these membrane mimetics can facilitate NMR studies on the structures and dynamics of membrane proteins. Cryogenic electron microscopy (cryo-EM) studies of the mitochondrial pyruvate carrier, MPC2, reconstituted into nanodiscs of synthetic copolymers has been used to solve the structure of this protein (Quesñay et al. 2020).

The Nanodisc platform provides a self-assembled system that renders typically insoluble protein targets, such as receptors, transporters, enzymes, and viral antigens, soluble in aqueous media in a native-like bilayer environment that maintain a target's functional activity (Sligar and Denisov 2021). By providing a bilayer surface of defined composition and structure, nanodiscs have found great utility in the study of cellular signaling complexes that assemble on a membrane surface. Nanodiscs provide a nanometer scale vehicle for the in vivo delivery of amphipathic drugs, therapeutic lipids, tethered nucleic acids, imaging agents and active protein complexes. This means of generating nanoscale lipid bilayers has spawned the successful use of numerous other polymer and peptide amphipathic systems (Sligar and Denisov 2021).

In some nanodiscs, the half torus, composed of short chain lipids, can be replaced by proteins (Dufourc 2021). This renders the nano-objects less fragile as they can be used to stabilize membrane protein assemblies to be studied, for example, by electron microscopy. Internal dynamics is similar to liposomes except that the phase transition is abolished, possibly due to lateral constrains imposed by the toroidal proteins limiting the disc size. Advantages and drawbacks of both nanoplatforms have been discussed (Dufourc 2021). Nanodiscs and other lipid-scaffolding polymers, such as styrene maleic acid (SMA) (see TC# 8.D.3), however, open new and promising avenues to explore the function-dynamics relationships of membrane proteins as well as between membrane proteins and their surrounding lipid environment (Bibow 2019). Saposin A picodiscs comprise a new platform broadly applicable to mass spectrometry studies of membrane proteins (Zhou et al. 2021).

Phospholipid bilayer nanodiscs are stable and tunable membrane mimetic for the study of membrane proteins (Padmanabha Das et al. 2020). The size of the nanodiscs that can be produced is usually limited to ~ 16 nm. Advances in nanodisc engineering such as covalently circularized nanodiscs (cND) and DNA corralled nanodiscs (DCND) have opened up the possibility of engineering nanodiscs of size up to 90 nm. This enables widening the application of nanodiscs from single membrane proteins to investigating large protein complexes and biological processes such as virus-membrane fusion and synaptic vesicle fusion (Nasr 2020). Another aspect of exploiting the large available surface area of these nanodiscs could be to engineer more realistic membrane mimetic systems with features such as membrane asymmetry and curvature. Padmanabha Das et al. 2020 discuss technical developments in nanodisc technology, leading to construction of large nanodiscs, and they examine some of the implicit applications. 

Mechanotransduction processes occur during magnetomechanical neuromodulation mediated by magnetic nanodiscs (Gomez et al. 2023). Magnetic nanotechnologies have emerged as non-invasive neuromodulation approaches with high spatiotemporal control. Gomez et al. 2023 developed a wireless force-induced neurostimulation platform utilizing micro-sized magnetic discs (MDs) and low-intensity alternating magnetic fields (AMFs). When targeted to the cell membrane, MDs AMFs-triggered mechanoactuation enhances specific cell membrane receptors resulting in cell depolarization. Neuronal activity in primary rat cortical neurons is evoked by the AMFs-triggered actuation of targeted MDs. Ion channel chemical inhibition suggests that magnetomechanical neuromodulation results from MD actuation on Piezo1 and TRPC1 mechanosensitive ion channels. The actuation mechanisms depend on MDs size, with cell membrane stretch and stress caused by the MDs torque being the most dominant (Gomez et al. 2023).

References associated with 8.D.4 family:

Bibow, S. (2019). Opportunities and Challenges of Backbone, Sidechain, and RDC Experiments to Study Membrane Protein Dynamics in a Detergent-Free Lipid Environment Using Solution State NMR. Front Mol Biosci 6: 103. 31709261
Brown, C.J., C. Trieber, and M. Overduin. (2021). Structural biology of endogenous membrane protein assemblies in native nanodiscs. Curr. Opin. Struct. Biol. 69: 70-77. [Epub: Ahead of Print] 33915422
Dufourc, E.J. (2021). Bicelles and nanodiscs for biophysical chemistry. Biochim. Biophys. Acta. Biomembr 1863: 183478. 32971065
Gomez, A., N. Muzzio, A. Dudek, A. Santi, C. Redondo, R. Zurbano, R. Morales, and G. Romero. (2023). Elucidating Mechanotransduction Processes During Magnetomechanical Neuromodulation Mediated by Magnetic Nanodiscs. Cell Mol Bioeng 16: 283-298. 37811002
Klöpfer, K. and F. Hagn. (2019). Beyond detergent micelles: The advantages and applications of non-micellar and lipid-based membrane mimetics for solution-state NMR. Prog Nucl Magn Reson Spectrosc 114-115: 271-283. 31779883
Nasr, M.L. (2020). Large nanodiscs going viral. Curr. Opin. Struct. Biol. 60: 150-156. 32066086
Padmanabha Das, K.M., W.M. Shih, G. Wagner, and M.L. Nasr. (2020). Large Nanodiscs: A Potential Game Changer in Structural Biology of Membrane Protein Complexes and Virus Entry. Front Bioeng Biotechnol 8: 539. 32596222
Quesñay, J.E.N., N.L. Pollock, R.S.K. Nagampalli, S.C. Lee, V. Balakrishnan, S.M.G. Dias, I. Moraes, T.R. Dafforn, and A.L.B. Ambrosio. (2020). Insights on the Quest for the Structure-Function Relationship of the Mitochondrial Pyruvate Carrier. Biology (Basel) 9:. 33227948
Sligar, S.G. and I.G. Denisov. (2021). Nanodiscs: A toolkit for membrane protein science. Protein. Sci. 30: 297-315. 33165998
Zhou, F., Y. Yang, S. Chemuru, W. Cui, S. Liu, M. Gross, and W. Li. (2021). Footprinting Mass Spectrometry of Membrane Proteins: Ferroportin Reconstituted in Saposin A Picodiscs. Anal Chem 93: 11370-11378. 34383472