Regulatory mechanisms triggered by enzyme interactions with lipid membrane surfaces

Abstract

Recruitment of enzymes to intracellular membranes often modulates their catalytic activity, which can be important in cell signaling and membrane trafficking. Thus, re-localization is not only important for these enzymes to gain access to their substrates, but membrane interactions often allosterically regulate enzyme function by inducing conformational changes across different time and amplitude scales. Recent structural, biophysical and computational studies have revealed how key enzymes interact with lipid membrane surfaces, and how this membrane binding regulates protein structure and function. This review summarizes the recent progress in understanding regulatory mechanisms involved in enzyme-membrane interactions.

Keywords: allosteric regulation; conformational change; lipid kinase; lipid metabolism; phosphatidylinositol phosphate lipids; protein-membrane interactions; signaling.

FIGURE 1

Structures of important membrane lipids. The inositol ring is numbered in phosphoinositol-4-phosphate (PI4P), as different hydroxyl groups can be phosphorylated to generate different phosphoinositide lipids (PIPs). PIPs can also be phosphorylated at more than one position. For example, PI(4,5)P₂ represents phosphorylation at both the 4- and 5-positions. Different internal membranes are enriched in different PIP lipids, and some PIP-interacting domains may have increased affinity for PIPs phosphorylated at specific positions.

FIGURE 2

Schematic illustration of CCT activation. The CCT enzyme is kept in an autoinhibited state until interactions with the membrane lead to a series of conformational changes, which enables the amphipathic M domain to interact with the membrane.

FIGURE 3

Lipid binding domains on the membrane with their putative membrane-binding pose. PKCδ C1 domain with Zn²⁺ and phorbol-1,3-acetate (PDB entry 1PTR). PKCα C2 domain with Ca²⁺ and phosphatidylserine (PDB entry 1DSY). PLCδ1 PH domain with inositol trisphosphate (PDB entry 1MAI). Sgk3 PX domain (PDB entry 6EDX). FAK FERM domain (PDB entry 2AL6).

FIGURE 4

Schematic illustration of PKCβII activation. In the open, inactive form, the C2 domain binds PI(4,5)P₂ and phosphatidylserine, but the DAG site in C1B is blocked. Phosphorylation and Ca²⁺ binding induces a series of conformational changes that allows the C1B to engage with DAG. These events lead to the activation of PKC. This figure was adapted in part from ref. Antal et al. (2015).

FIGURE 5

Schematic illustration of PTEN activation. PTEN remains in an autoinhibited state until removal of phosphate groups in the C-terminal region, which then allows membrane interaction. Specific interactions include C2 domain interacting with phosphatidylserine and the PBD domain interacting with PI(4,5)P₂, which then allows the phosphatase domain to gain access to its PI(3,4,5)P₃ substrate. This figure was adapted in part from ref. Jang et al. (2021).

FIGURE 6

Schematic illustration of PKB/Akt activation. Phosphorylation at positions 308 and 473 releases the PH domain so that it can interact with PIP lipids in the membrane.

FIGURE 7

Schematic illustration of Btk activation. A series of conformational changes, including changes in domain-domain interactions, must occur to allow the PH-TH domain to interact with PI(3,4,5)P₃. There is a proposed intermediate state that interacts with the membrane, but further conformational changes, dimerization and trans-autophosphorphorylation are required for full activation. This figure was adapted in part from ref. Kueffer et al. (2021).

FIGURE 8

Schematic illustration of FAK activation. Activation of FAK requires dimerization to release the kinase domain and allow for domain reorientation. FAK can further oligomerize upon trans-phosphorylation. This figure was adapted in part from ref. Acebrón et al. (2020).