biostudies-literatureLong MJCSwiss National Science FoundationNIH Office of the DirectorNIGMS NIH HHS42-55https://www.ebi.ac.uk/biostudies/studies/S-EPMC8341840biostudies-literatureUnknown1(2)Transient associations between numerous organelles-<i>e.g.</i>, the endoplasmic reticulum and the mitochondria-forge highly-coordinated, particular environments essential for cross-compartment information flow. Our perspective summarizes chemical-biology tools that have enabled identifying proteins present within these itinerant communities against the bulk proteome, even when a particular protein's presence is fleeting/substoichiometric. However, proteins resident at these ephemeral junctions also experience transitory changes to their interactomes, small-molecule signalomes, and, importantly, functions. Thus, a thorough census of sub-organellar communities necessitates functionally probing context-dependent signaling properties of individual protein-players. Our perspective accordingly further discusses how repurposing of existing tools could allow us to glean a functional understanding of protein-specific signaling activities altered as a result of organelles pulling together. Collectively, our perspective strives to usher new chemical-biology techniques that could, in turn, open doors to modulate functions of specific subproteomes/organellar junctions underlying the nuanced regulatory subsystem broadly termed as contactology.RSC chemical biologyNeighborhood watch: tools for defining locale-dependent subproteomes and their contextual signaling activities.PMC8341840190192DP2 GM114850184729NIH 1DP2GM114850Aye YZhao YLong MJCfalseNeighborhood watch: tools for defining locale-dependent subproteomes and their contextual signaling activities.Transient associations between numerous organelles-<i>e.g.</i>, the endoplasmic reticulum and the mitochondria-forge highly-coordinated, particular environments essential for cross-compartment information flow. Our perspective summarizes chemical-biology tools that have enabled identifying proteins present within these itinerant communities against the bulk proteome, even when a particular protein's presence is fleeting/substoichiometric. However, proteins resident at these ephemeral junctions also experience transitory changes to their interactomes, small-molecule signalomes, and, importantly, functions. Thus, a thorough census of sub-organellar communities necessitates functionally probing context-dependent signaling properties of individual protein-players. Our perspective accordingly further discusses how repurposing of existing tools could allow us to glean a functional understanding of protein-specific signaling activities altered as a result of organelles pulling together. Collectively, our perspective strives to usher new chemical-biology techniques that could, in turn, open doors to modulate functions of specific subproteomes/organellar junctions underlying the nuanced regulatory subsystem broadly termed as contactology.2020-01-01T00:00:00Z2020 Jun2025-04-04T19:42:42.793Z2022-02-11T10:03:53.574ZS-EPMC83418403445874710.1039/d0cb00041h