Principles of Transporter Function | Research | Beckstein Lab

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Principles of Transporter Function

Principles of Transporter Function

Transport of ions and small molecules across the cell membrane against electrochemical gradients is catalyzed by integral membrane proteins that use a source of free energy to drive the energetically uphill flux of the transported substrate. Secondary active transporters couple the spontaneous influx of a “driving” ion such as Na+ or H+ to the flux of the substrate.

The thermodynamics of such cyclical non-equilibrium systems are well understood and recent work has focused on the molecular mechanism of secondary active transport. The fact that these transporters change their conformation between an inward-facing and outward-facing conformation in a cyclical fashion, called the alternating access model, is broadly recognized as the molecular framework in which to describe transporter function.

However, only with the advent of high resolution crystal structures and detailed computer simulations has it become possible to recognize common molecular-level principles between disparate transporter families. Inverted repeat symmetry in secondary active transporters has shed light on how protein structures can encode a bi-stable two-state system.

More detailed analysis (based on experimental structural data and detailed molecular dynamics simulations) indicates that transporters can be understood as gated pores with at least two coupled gates. These gates are not just a convenient cartoon element to illustrate a putative mechanism but map to distinct parts of the transporter protein. Enumerating all distinct gate states naturally includes occluded states in the alternating access picture and also suggests what kind of protein conformations might be observable. By connecting the possible conformational states and ion/substrate bound states in a kinetic model, a unified picture emerges in which symporter, antiporter, and uniporter function are extremes in a continuum of functionality.

Read more: arXiv:1912.06275 [q-bio.BM]

Alternating access from the broken symmetry of inverted repeats.

Alternating access from the broken symmetry of inverted repeats. Two symmetry-broken inverted repeats (A and B) can generate the two major conformations of the alternating access model by swapping their conformation. (Image by Fiona Naughton).

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