NLRs and STANDs: a class of enthalpy and entropy dual-driven allosteric switches varying information entropies

NLRs (NOD-like receptors) and their STAND (signal transduction ATPases with numerous domains) homologs represent a class of widespread, sophisticated signaling hubs, which function as allosteric switches to control various biological processes, including immune responses, apoptosis, tumorigenesis, cell stemness, gene expression, DNA damage repair and plant pathogen resistance. Over the past two decades, remarkable progress in structural studies has generated a wealth of data on these proteins. However, while the regulation of these allosteric switches encompasses both structural conformations and thermodynamic properties, the latter aspect remains largely unexplored. This review begins with a brief overview of recent advances in their structural and allosteric regulation, with a particular focus on how the decreased enthalpy and increased entropy likely drive the OFF-to-ON switching. Furthermore, the varying Shannon entropies during OFF-to-ON switching suggest that the fidelity of these molecular switches is never absolute but rather adapts to evolving conditions. The analyses and discussions offer new insights into how biochemical, thermodynamic, and informatic principles act in concert to shape cellular signaling, and potentially guide the future design of synthetic biochemical switches.