Every Detail Matters. That Is, How the Interaction between Gα Proteins and Membrane Affects Their Function

Abstract

In highly organized multicellular organisms such as humans, the functions of an individual cell are dependent on signal transduction through G protein-coupled receptors (GPCRs) and subsequently heterotrimeric G proteins. As most of the elements belonging to the signal transduction system are bound to lipid membranes, researchers are showing increasing interest in studying the accompanying protein-lipid interactions, which have been demonstrated to not only provide the environment but also regulate proper and efficient signal transduction. The mode of interaction between the cell membrane and G proteins is well known. Despite this, the recognition mechanisms at the molecular level and how the individual G protein-membrane attachment signals are interrelated in the process of the complex control of membrane targeting of G proteins remain unelucidated. This review focuses on the mechanisms by which mammalian Gα subunits of G proteins interact with lipids and the factors responsible for the specificity of membrane association. We summarize recent data on how these signaling proteins are precisely targeted to a specific site in the membrane region by introducing well-defined modifications as well as through the presence of polybasic regions within these proteins and interactions with other components of the heterocomplex.

Keywords: G proteins; G-protein-coupled receptors; GTP-binding proteins; lipids; membrane domains; signal transduction.

Figure 1

Sequence alignment of the N-terminal region of selected human Gα subunits. The residues are colored to indicate their modifications or properties: green—N-myristoylated glycine residue (for Gαs N-palmitoylated glycine); orange—S-palmitoylated cysteine; blue—residues with a positive charge.

Figure 2

Localization of positively charged amino acid residues (blue balls and sticks) of the N-terminal fragment in the context of the tertiary and quaternary structure of Gαsβ₁γ₂ heterotrimer and Gαi₁ subunit (red). The Gαs is colored green; the Gβ₁ is orange; the Gγ₂–yellow. The diagram was generated using coordinates from the PDB: 6X18 and 6CRK and visualized with BIOVIA Discovery Studio 4.0.