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8.D.3. The Polystyrene-Malic Acid Copolymer Particle/Nanodisc (PMACP) Family

Nanoparticles assembled with poly(styrene-maleic acid) copolymers, identified in the literature as Lipodisq, SMALPs or Native Nanodisc, are routinely used as membrane mimetics to stabilize integral membrane proteins and other structures in their native conformations (Bada Juarez et al. 2019). Transmembrane proteins of varying complexity (up to 8 beta strands or 48 alpha helices) and of a range of molecular weights (from 27 kDa up to 500 kDa) have been incorporated into these particles  for structural and functional studies. Related amphipathic polymers have become versatile components of the biochemist's tool kit for the stabilization, extraction and structural characterization of membrane proteins by techniques including cryo-EM and X-ray crystallography (Autzen et al. 2019). These procedures do not require the use of conventional detergents and thus avoids their associated detrimental consequences (Bada Juarez et al. 2019).

Membrane proteins work within asymmetric bilayers of lipid molecules, but associations are lost when detergents dislodge lipids, ligands and subunits. They are often 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 (memteins). Overduin et al. 2021 reviewed the structures and mechanisms of transmembrane targets and their interactions with lipids including phosphoinositides (PIs), as resolved using nanodisc systems and methods including cryo-EM and X-ray diffraction (XRD). 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 arre considered.

References associated with 8.D.3 family:

Autzen, H.E., D. Julius, and Y. Cheng. (2019). Membrane mimetic systems in CryoEM: keeping membrane proteins in their native environment. Curr. Opin. Struct. Biol. 58: 259-268. 31279500
Bada Juarez, J.F., A.J. Harper, P.J. Judge, S.R. Tonge, and A. Watts. (2019). From polymer chemistry to structural biology: The development of SMA and related amphipathic polymers for membrane protein extraction and solubilisation. Chem Phys Lipids 221: 167-175. 30940445
Overduin, M., C. Trieber, R.S. Prosser, L.P. Picard, and J.G. Sheff. (2021). Structures and Dynamics of Native-State Transmembrane Protein Targets and Bound Lipids. Membranes (Basel) 11:. 34204456