Abstract
Proteomics has revealed that many proteins are present in unexpected cellular locations. Moreover, it is increasingly recognized that proteins can translocate between intracellular and extracellular compartments in non-conventional ways. This increases gene pleiotrophy as the diverse functions of the protein that the gene encodes are dependent on the cellular location. Given that trafficking drug targets may exist in various forms — often with completely different functions — in multiple cellular compartments, careful interpretation of proteomics data is needed for an accurate understanding of gene function. This Perspective is intended to inspire the investigation of unusual protein localizations, rather than assuming that they are due to mislocalization or artefacts. Given a fair chance, proteomics could reveal novel and unforeseen biology with important ramifications for target validation in drug discovery.
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Butler, G. S. & Overall, C. M. Updated biological roles for matrix metalloproteinases and new “intracellular” substrates revealed by degradomics. Biochemistry (9 Oct 2009) (doi:10.1021/bi901656f).
Acknowledgements
C.M.O. is supported by a Canada Research Chair in Metalloproteinase Proteomics and Systems Biology. This research was supported by grants from the Canadian Institutes of Health Research, the National Cancer Institute of Canada (with funds raised by the Canadian Cancer Association), a Special Program Grant from the Canadian Breast Cancer Research Alliance Metastasis, and a Centre Grant from the Michael Smith Research Foundation to the University of British Columbia Centre for Blood Research.
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Glossary
- Drug target
-
A molecule that is known to be involved in disease against which a drug is designed to block these pathological actions.
- Pharmacoproteomics
-
The proteomic characterization of the effects of a drug on a system.
- Anti-target
-
A molecule that must be therapeutically spared owing to host-protective effects in a disease, or the blockade of which produces unacceptable side effects.
- Counter-target
-
A molecule that might reduce the efficiency of a drug.
- Off-target
-
A molecule that interacts with a drug but is not the intended target of the drug.
- Shotgun proteomics
-
High-throughput proteomics using high-performance liquid chromatography and mass spectrometry to identify peptides generated from a proteome — for example, by trypsin — from which the protein components are identified.
- Chemical proteomics
-
The identification of small-molecule interactors in a complex sample using affinity capture.
- Target refinement
-
By mapping the network in which a drug target lies, alternative targets at different points in the pathway, which have the desired effect but with greater specificity, may be selected.
- Degradomics
-
The identification of all proteases, their substrates and inhibitors by genomics and proteomics techniques.
- Secretome
-
The portion of the proteome that is secreted.
- Sheddase
-
A protease that releases or 'sheds' all or a portion of a protein to the extracellular milieu.
- Neoproteins
-
Functional proteins that are released from a larger protein by specific proteolysis.
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Butler, G., Overall, C. Proteomic identification of multitasking proteins in unexpected locations complicates drug targeting. Nat Rev Drug Discov 8, 935–948 (2009). https://doi.org/10.1038/nrd2945
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DOI: https://doi.org/10.1038/nrd2945
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