Getting a grip on StAR-related lipid-transfer (START) domain proteins in bacteria
TL;DR
It is suggested that bacterial START domains participate in a remarkably broad range of biological processes-including small-molecule binding, metabolic regulation, enzymatic catalysis, and stress adaptation-rather than traditional lipid transport.
Abstract
Abstract StAR-related lipid transfer (START) domain proteins comprise a conserved superfamily defined by a characteristic helix-grip fold that enables the binding of hydrophobic ligands. In mammals, START domain proteins have been extensively characterized as key mediators of nonvesicular lipid transport and lipid-dependent signalling pathways. In contrast, the prevalence, structural diversity, and functional roles of START domain proteins in bacteria remain underexplored and for those that are characterized, experimental findings are occasionally conflicting. While bacterial START domains preserve the core helix-grip fold for lipid binding, they are typically smaller and exhibit more limited conformational flexibility than their eukaryotic counterparts. Despite these apparent constraints, available experimental data suggest that bacterial START domains participate in a remarkably broad range of biological processes—including small-molecule binding, metabolic regulation, enzymatic catalysis, and stress adaptation—rather than traditional lipid transport. Bacteria within the phylum Actinomycetota, in particular, have evolved a prolific repertoire of START-domain proteins. As an example, we will discuss the START domain proteins of Mycobacterium tuberculosis in detail, one of which has emerged as a promising drug target. Collectively, this synthesis underscores the functional versatility of the START domain across the domains of life and identifies critical knowledge gaps that warrant further investigation.
