The changing landscape of membrane protein structural biology through developments in electron microscopy

Abstract

Membrane proteins are ubiquitous in biology and are key targets for therapeutic development. Despite this, our structural understanding has lagged behind that of their soluble counterparts. This review provides an overview of this important field, focusing in particular on the recent resurgence of electron microscopy (EM) and the increasing role it has to play in the structural studies of membrane proteins, and illustrating this through several case studies. In addition, we examine some of the challenges remaining in structural determination, and what steps are underway to enhance our knowledge of these enigmatic proteins.

Keywords: Electron microscopy; membrane protein; protein structure.

Figure 1.

Examples of sub nm membrane protein structures determined by cryo-EM. Examples showing EM reconstructions of RyR1 (EMDB-2807), Piezo1 (EMDB-6343), γ-secretase (EMDB-3061) and Ca_v1.1 (EMDB-6475) (grey density) with fitted atomic models. This Figure is reproduced in colour in Molecular Membrane Biology online.

Figure 2.

Mean resolution vs year of deposition within the EMDB. Analysis of the average resolution of deposited membrane protein structures within the EMDB in each year is shown in black. Highest resolution reconstruction deposited each year is show in grey. The general trend shows the resolution steadily increasing over time.

Figure 3.

Increasing resolution of the ATPase family structures from EM. (A) F-ATPase structures determined by EM from ∼32 Å to 6.4 Å (EMDB accession codes: 1357,2091,3169). (B) A-ATPase structures determined by EM from ∼16–6.4 Å (EMDB accession codes: 1888,5335,8016). (C) V-ATPase structures determined by EM from ∼17–6.9 Å (EMDB accession codes: 1590,5476,6284). This Figure is reproduced in colour in Molecular Membrane Biology online.