Maintaining the Integral Membrane Proteome: Revisiting the Functional Repertoire of Integral Membrane Proteases

Cells in all kingdoms of life employ dedicated protein quality control machineries for both their cytosolic and membrane proteome ensuring cellular functionality. These crucial systems consist besides a large variety of molecular chaperones, ensuring a proper fold and consequently function of the client's proteome, of several proteases to clean out damaged, unfunctional and potentially toxic proteins. One of the key features underlying the functional cycle of these quality control systems is the inherent flexibility of their bound clients which for a long time impaired detailed structural characterization, with advanced high-resolution NMR spectroscopy in the last decade playing a key role contributing to the present understanding of their functional properties. Although these studies laid the foundation of the present knowledge of the mechanistic details of the maintenance of cytosolic proteins, the understanding of related systems employed for membrane associated as well as integral membrane proteins remains rather sparse to date. Herein, we review the crucial contributions of structural and dynamical biology approaches, possessing the power to resolve both structure and dynamics of such systems as well as enabling the elucidation of the functional repertoire of multimeric proteases involved in maintaining a functional membrane proteome.