Membrane Protein Complexity Revealed Through Native Mass Spectrometry

In all living organisms, membrane proteins play a crucial role in governing essential biological functions, such as cellular signaling and molecular transport. These functions rely on intricate interactions with a variety of biomolecules, including substrates, proteins, metabolites, and lipids. Any disruption or alteration to these interactions can result in disease. Therefore, comprehending the complex assemblies of membrane proteins, and their intrinsic interactions, is crucial for unraveling the mechanisms of cellular regulation and has implications in disease pathology. Over the past three decades, native mass spectrometry (MS) has emerged as a pivotal tool for investigating the structure and dynamics of proteins, including membrane protein complexes. In this review, we discuss recent developments in instrumentation that advance our ability to characterize membrane proteins in their native context. As we transition toward increasingly complex eukaryotic systems, we show how this information is translated into an understanding of disease. We also highlight preliminary studies in which native MS has been used to sequence and localize membrane protein complexes within endogenous tissue. This level of detail offers the promise of informing about the molecular mechanisms of disease states.