Large-scale state-dependent membrane remodeling by a transporter protein

Elife. 2019 Dec 19;8:e50576. doi: 10.7554/eLife.50576.

Abstract

That channels and transporters can influence the membrane morphology is increasingly recognized. Less appreciated is that the extent and free-energy cost of these deformations likely varies among different functional states of a protein, and thus, that they might contribute significantly to defining its mechanism. We consider the trimeric Na+-aspartate symporter GltPh, a homolog of an important class of neurotransmitter transporters, whose mechanism entails one of the most drastic structural changes known. Molecular simulations indicate that when the protomers become inward-facing, they cause deep, long-ranged, and yet mutually-independent membrane deformations. Using a novel simulation methodology, we estimate that the free-energy cost of this membrane perturbation is in the order of 6-7 kcal/mol per protomer. Compensating free-energy contributions within the protein or its environment must thus stabilize this inward-facing conformation for the transporter to function. We discuss these striking results in the context of existing experimental observations for this and other transporters.

Keywords: enhanced sampling; membrane morphology; membrane transport; molecular biophysics; molecular simulation; none; structural biology; thermodynamics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aspartic Acid / metabolism
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Energy Metabolism*
  • Ions / chemistry
  • Ions / metabolism
  • Molecular Dynamics Simulation
  • Protein Conformation*
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • Pyrococcus horikoshii / chemistry
  • Sodium / metabolism*
  • Symporters / genetics*
  • Symporters / metabolism
  • Symporters / ultrastructure

Substances

  • Ions
  • Protein Subunits
  • Symporters
  • Aspartic Acid
  • Sodium

Associated data

  • PDB/2NWX
  • PDB/3KBC
  • PDB/5ULD

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.