Homogeneous nanodiscs of native membranes formed by stilbene–maleic-acid copolymers

Esmaili, Mansoore; Brown, Chanelle J.; Shaykhutdinov, Rustem; Acevedo-Morantes, Claudia Y.; Wang, Yong Liang; Wille, Holger; Gandour, Richard D.; Turner, S. Richard; Overduin, Michael

doi:10.1039/d0nr03435e

Cited by 31 publications

(32 citation statements)

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“…Recent studies have successfully demonstrated the use of synthetic polymers to directly extract membrane proteins and reconstitute them in near-native lipid bilayer nanodiscs without using a detergent. [1][2][3][4][5][6][7] However, the presence of charge on the currently known polymers drastically limits their applications. [8,9] The high charge density of the polymer interferes with the purification by ion-exchange chromatography and also detrimental to study oppositely charged membrane proteins due to charge-charge interactions.…”

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confidence: 99%

Synthesis, Characterization, and Nanodisc Formation of Non‐ionic Polymers**

Ravula

Ramamoorthy

2021

Angewandte Chemie

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Although lipid nanodiscs are increasingly used in the structural studies of membrane proteins, drug delivery and other applications, the interaction between the nanodisc belt and the protein to be reconstituted is a major limitation. To overcome this limitation and to further broaden the scope of nanodiscs, a family of non-ionic amphiphilic polymers synthesized by hydrophobic functionalization of fructo-oligosaccharides/inulin is reported. We show the stability of lipid nanodiscs formed by these polymers against pH and divalent metal ions, and their magnetic-alignment properties. The reported results also demonstrate that the non-ionic polymers extract membrane proteins with unprecedented efficiency.

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confidence: 99%

Synthesis, Characterization, and Nanodisc Formation of Non‐ionic Polymers**

Ravula

Ramamoorthy

2021

Angewandte Chemie

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“…The use of methyl-substituted stilbenes in copolymerization reactions (rather than styrene) along with maleic anhydride generates STMA copolymers that possess semi-rigid backbones [ 100 , 101 , 102 ]. The unique composition, sequence distribution, and backbone rigidity of these copolymers confer broader pH utility and more homogeneous nanodisc sizes and shapes, as demonstrated with the E. coli membrane protein PagP [ 12 ]. Further development of such copolymers will enable a continued growth of this field as a wider diversity of membranes, tissues and targets can be exploited for an expanding range of applications.…”

Section: Polymer Design For Native Nanodiscsmentioning

confidence: 99%

“…The hydrolyzed derivatives of styrene maleic anhydride include styrene- co -maleic acid (SMA) [ 4 ], styrene- alt -maleamic acid (SMA-MA) [ 5 ], SMA ethanolamine (SMA-EA) [ 6 ], SMA ethylenediamine (SMA-ED) [ 7 ], SMA with sulfhydrils (SMA-SH), [ 8 ], SMA with taurine (SMA-Tau) [ 9 ], styrene-co-maleimide (SMI) [ 10 ], styrene maleimide quaternary ammonium (SMA-QA) [ 11 ], and dehydrated SMA ethylenediamine copolymer (SMAd-A). The analogues of SMA include poly(2-methylstilbene-alt-maleic anhydride) (2-STMA), poly(4-methylstilbene-alt-maleic anhydride) (4-STMA) [ 7 , 12 ], acrylic acid- co -styrene (AASTY) [ 13 ], zwitterionic SMA (zSMA) [ 14 ], alkyl polyacrylic acid (APAA) [ 15 ], polymethacrylate (PMA) [ 16 ], and diisobutylene- alt -maleic acid (DIBMA) [ 17 ] as well as its glycerol- and glucosamine-containing derivatives.…”

Section: Figurementioning

confidence: 99%

Structures and Dynamics of Native-State Transmembrane Protein Targets and Bound Lipids

et al. 2021

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Membrane proteins work within asymmetric bilayers of lipid molecules that are critical for their biological structures, dynamics and interactions. These properties are lost when detergents dislodge lipids, ligands and subunits, but are maintained in native nanodiscs formed using styrene maleic acid (SMA) and diisobutylene maleic acid (DIBMA) copolymers. These amphipathic polymers allow extraction of multicomponent complexes of post-translationally modified membrane-bound proteins directly from organ homogenates or membranes from diverse types of cells and organelles. Here, we review the structures and mechanisms of transmembrane targets and their interactions with lipids including phosphoinositides (PIs), as resolved using nanodisc systems and methods including cryo-electron microscopy (cryo-EM) and X-ray diffraction (XRD). We focus on therapeutic targets including several G protein-coupled receptors (GPCRs), as well as ion channels and transporters that are driving the development of next-generation native nanodiscs. The design of new synthetic polymers and complementary biophysical tools bodes well for the future of drug discovery and structural biology of native membrane:protein assemblies (memteins).

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“…Sharing similarities in monomer chemical structure with SMA, methyl functionalised poly(stilbene-co-maleic acids) in Figure 3c), have been demonstrated as efficient for solubilising synthetic and native cellular membrane components into nanodiscs within the expanded pH range of 5-10. [71] More interesting advantages of STMAs, however, are conferred from their strictly alternating sequence owing to the inability for either monomer to homopolymerise as well as the increased rigidity of the polymer backbone. Precise regulation over the sequence and length of polymer chains for synthesised STMA copolymers resulted in an enhanced homogeneity of size (~20 nm) and structure of assembled nanodiscs.…”

Section: Other Nanodisc Forming Polymersmentioning

confidence: 99%

Polymer Nanodiscs and Their Bioanalytical Potential

Farrelly

Martin

Thang

2021

Chemistry A European J

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Membrane proteins (MPs) play a pivotal role in cellular function and are therefore predominant pharmaceutical targets. Although detailed understanding of MP structure and mechanistic activity is invaluable for rational drug design, challenges are associated with the purification and study of MPs. This review delves into the historical developments that became the prelude to currently available membrane mimetic technologies before shining a spotlight on polymer nanodiscs. These are soluble nanosized particles capable of encompassing MPs embedded in a phospholipid ring. The expanding range of reported amphipathic polymer nanodisc materials is presented and discussed in terms of their tolerance to different solution conditions and their nanodisc properties. Finally, the analytical scope of polymer nanodiscs is considered in both the demonstration of basic nanodisc parameters as well as in the elucidation of structures, lipidprotein interactions, and the functional mechanisms of reconstituted membrane proteins. The final emphasis is given to the unique benefits and applications demonstrated for native nanodiscs accessed through a detergent free process.

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Homogeneous nanodiscs of native membranes formed by stilbene–maleic-acid copolymers

Abstract: Methylstilbene-alt-maleic acid copolymers spontaneously convert biological membranes into bilayer discs with ∼20 nm diameters.

Cited by 31 publications

References 31 publications

Synthesis, Characterization, and Nanodisc Formation of Non‐ionic Polymers**

Synthesis, Characterization, and Nanodisc Formation of Non‐ionic Polymers**

Structures and Dynamics of Native-State Transmembrane Protein Targets and Bound Lipids

Polymer Nanodiscs and Their Bioanalytical Potential

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