Abstract
A better understanding of the molecular mechanisms underlying disease is key for expediting the development of novel therapeutic interventions. Disease mechanisms are often mediated by interactions between proteins. Insights into the physical rewiring of protein–protein interactions in response to mutations, pathological conditions, or pathogen infection can advance our understanding of disease etiology, progression, and pathogenesis and can lead to the identification of potential druggable targets. Advances in quantitative mass spectrometry (MS)‐based approaches have allowed unbiased mapping of these disease‐mediated changes in protein–protein interactions on a global scale. Here, we review MS techniques that have been instrumental for the identification of protein–protein interactions at a system‐level, and we discuss the challenges associated with these methodologies as well as novel MS advancements that aim to address these challenges. An overview of examples from diverse disease contexts illustrates the potential of MS‐based protein–protein interaction mapping approaches for revealing disease mechanisms, pinpointing new therapeutic targets, and eventually moving toward personalized applications.
Highlights
Identifying the principal molecular basis of human diseases is crucial for successful prevention, diagnosis, and treatment
Nodes are connected by edges to the interacting proteins identified by Affinity Purification Mass Spectrometry (AP-mass spectrometry (MS)), proximity labeling, Cross-Linking Mass Spectrometry (XL-MS), or other types of experiments
These data can be further integrated with structural information obtained from cryo-EM or XL-MS or functionally analyzed using genetic interaction maps, ideally placing complexes into pathways and providing clues on their mechanisms
Summary
Identifying the principal molecular basis of human diseases is crucial for successful prevention, diagnosis, and treatment. Nodes are connected by edges to the interacting proteins identified by Affinity Purification Mass Spectrometry (AP-MS), proximity labeling, Cross-Linking Mass Spectrometry (XL-MS), or other types of experiments This mapping is performed in both the diseased state and non-diseased or WT states, and variations between the global regulation of PPIs in the networks are monitored. Using large-scale host–pathogen interaction studies to develop host-directed strategies promises to reveal more broadly acting antivirals with reduced potential for viral escape (Batra et al, 2018; Shah et al, 2018) This approach can be used for exploring drug repurposing, where drugs already approved for treatment of a specific disease may target the same proteins implicated in another disease. Citation Kobayashi et al (2019) Kazazian et al (2017) Luo et al (2018) Zhu et al (2019) Thuault et al (2020) Kothari et al (2020) Okuyama et al (2019) Kim et al (2017) Manshouri et al (2019) Reina-Campos et al (2019) Hauri et al (2013) O’Connor et al (2020) Waldron et al (2016) Chu et al (2018) Chiang et al (2018) Zhang et al (2018) Li et al (2015) Shirasaki et al (2012) Chou et al (2018) Malty et al (2017) Hosp et al (2015)
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