Lipids in the Assembly of Membrane Proteins and Organization of Protein Supercomplexes: Implications for Lipid-linked Disorders

Abstract

Lipids play important roles in cellular dysfunction leading to disease. Although a major role for phospholipids is in defining the membrane permeability barrier, phospholipids play a central role in a diverse range of cellular processes and therefore are important factors in cellular dysfunction and disease. This review is focused on the role of phospholipids in normal assembly and organization of the membrane proteins, multimeric protein complexes, and higher order supercomplexes. Since lipids have no catalytic activity, it is difficult to determine their function at the molecular level. Lipid function has generally been defined by affects on protein function or cellular processes. Molecular details derived from genetic, biochemical, and structural approaches are presented for involvement of phosphatidylethanolamine and cardiolipin in protein organization. Experimental evidence is presented that changes in phosphatidylethanolamine levels results in misfolding and topological misorientation of membrane proteins leading to dysfunctional proteins. Examples are presented for diseases in which proper protein folding or topological organization is not attained due to either demonstrated or proposed involvement of a lipid. Similar changes in cardiolipin levels affects the structure and function of individual components of the mitochondrial electron transport chain and their organization into supercomplexes resulting in reduced mitochondrial oxidative phosphorylation efficiency and apoptosis. Diseases in which mitochondrial dysfunction has been linked to reduced cardiolipin levels are described. Therefore, understanding the principles governing lipid-dependent assembly and organization of membrane proteins and protein complexes will be useful in developing novel therapeutic approaches for disorders in which lipids play an important role.

An essential bacterial-type cardiolipin synthase mediates cardiolipin formation in a eukaryote

“…In eukaryotes, CL is required for proper function of key mitochondrial enzymes and proteins involved in oxidative phosphorylation and certain mitochondrial transport systems (reviewed in refs. [11][12][13]. Mitochondrial CL associates with respiratory complexes I (NADH-ubiquinone reductase) (14), III (ubiquinol-cytochrome c reductase) (15,16), IV (cytochrome oxidase) (17), and V (F o F 1 -ATPase) (18) and stabilizes supercomplexes consisting of respiratory complexes III and IV (19).…”

Alterations in phosphatidylethanolamine levels affect the generation of Aβ

“…Normal assembly of LacY occurs into E. coli membranes containing an abundance of PE. In contrast, depletion of PE leads to partial misfolding of the protein combined with partial loss of activity of LacY (Bogdanov et al, 2008). Thus, one could envision that PE also facilitates the folding of proteins of the c-complex into a fully native conformation by interacting with late folding and non-native intermediates, as do most conventional protein molecular chaperones.…”

An unusual phosphatidylethanolamine-utilizing cardiolipin synthase is discovered in bacteria

“…It was first isolated from beef heart as a serologically active phospholipid (1), hence the name cardiolipin. In animals, plants, and lower eukaryotic organisms (e.g., yeast), cardiolipin is a component of the inner mitochondrial membrane bilayer, where it plays an important role in the function of enzyme complexes involved in energy transduction and ATP synthesis (2,3). It is found in the membranes of Gram-positive and Gram-negative bacteria, where it also functions in energy production (2,3).…”

“…In animals, plants, and lower eukaryotic organisms (e.g., yeast), cardiolipin is a component of the inner mitochondrial membrane bilayer, where it plays an important role in the function of enzyme complexes involved in energy transduction and ATP synthesis (2,3). It is found in the membranes of Gram-positive and Gram-negative bacteria, where it also functions in energy production (2,3). The nature (i.e., chain length and degree of saturation) of the four acyl groups and the hydrophilic head group of this phospholipid have an impact on mitochondrial membrane structure and function, and, by extension, the roles this organelle plays in cell physiology (2,4).…”

“…It is found in the membranes of Gram-positive and Gram-negative bacteria, where it also functions in energy production (2,3). The nature (i.e., chain length and degree of saturation) of the four acyl groups and the hydrophilic head group of this phospholipid have an impact on mitochondrial membrane structure and function, and, by extension, the roles this organelle plays in cell physiology (2,4). Thus, how cardiolipin is synthesized, remodeled, and metabolized are important areas of investigation.…”