Subcellular Protein Localisation in Health and Disease

Abstract

The nonhomogeneous distribution of cellular components is an essential property of all cells. Macromolecules are generally not capable of freely diffusing throughout the cell. In addition, the eukaryotic cell is organised into membrane‐covered compartments that are characterised by different metabolic activities and specific proteins. The synthesis of proteins is confined to only one of these compartments, the cell cytosol. As proteins exert their functions in different organelles of the cell, protein translocation is a fundamental requirement of cell physiology. The asymmetry of cellular constituents is essential for cellular signalling and their aberrant localisation contributes to the pathogenesis in many human diseases. In this article, we provide an overview of mechanisms involved in physiological and pathological protein translocations. We provide examples for experimental procedure to investigate these mechanisms and discuss strategies to interfere with protein translocation mechanisms to treat diseases.

Key Concepts

  • In order to exert their function, proteins have to be at the right place at the right time.
  • The eukaryotic cell is a very crowded environment with many diffusion barriers.
  • Sophisticated mechanisms of protein trafficking to ensure accurate subcellular protein localisation have evolved.
  • Accurate protein trafficking can fail due to alterations such as mutations and post‐translational modifications at different levels of the transport pathways.
  • The resulting protein mislocalisation can lead to a broad variety of human diseases.
  • Significant technological progress has been made, allowing for unprecedented possibilities to monitor subcellular protein localisation.
  • Two therapeutic strategies to target protein localisation have emerged: Therapeutic restoration of physiological protein localisation and therapeutic mistargeting to inactivate disease‐causing proteins.

Keywords: target discovery; target validation; high content screening; imatinib; chemical genetics

Figure 1. Multiple immunofluorescence detection. In the figure, the protein under study and microtubules were detected by indirect immunofluorescence. DNA was detected by direct staining with the fluorescent dye DAPI. (Florindo and Tavares)
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Florindo, Claudia, Ferreira, Bibiana I, Serrão, Sónia M, Tavares, Álvaro A, and Link, Wolfgang(Feb 2016) Subcellular Protein Localisation in Health and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026534]