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Functions of intrinsic disorder in transmembrane proteins

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Abstract

Intrinsic disorder is common in integral membrane proteins, particularly in the intracellular domains. Despite this observation, these domains are not always recognized as being disordered. In this review, we will discuss the biological functions of intrinsically disordered regions of membrane proteins, and address why the flexibility afforded by disorder is mechanistically important. Intrinsically disordered regions are present in many common classes of membrane proteins including ion channels and transporters; G-protein coupled receptors (GPCRs), receptor tyrosine kinases and cytokine receptors. The functions of the disordered regions are many and varied. We will discuss selected examples including: (1) Organization of receptors, kinases, phosphatases and second messenger sources into signaling complexes. (2) Modulation of the membrane-embedded domain function by ball-and-chain like mechanisms. (3) Trafficking of membrane proteins. (4) Transient membrane associations. (5) Post-translational modifications most notably phosphorylation and (6) disorder-linked isoform dependent function. We finish the review by discussing the future challenges facing the membrane protein community regarding protein disorder.

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Fig. 1

Reproduced in a modified form from [43] available under a Creative Commons BY 4.0 license

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Figure modified from [179] with permission. Copyright (2014) Elsevier

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Acknowledgements

M.K is supported by Grants from the Villum Foundation and a COFUND fellowship from AIAS. B.B.K. is supported by the Danish Research Councils (DFF—4181-00344) and the Novo Nordisk Foundation SYNERGY program. Michael V. Clausen, Katie Kemplen, and Stine F. Petersen are thanked from critical comments to the manuscript.

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Authors and Affiliations

  1. Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus, Denmark

    Magnus Kjaergaard

  2. Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

    Magnus Kjaergaard

  3. Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark

    Magnus Kjaergaard

  4. The Danish Research Institute of Translational Neuroscience (DANDRITE), Aarhus, Denmark

    Magnus Kjaergaard

  5. Structural Biology and NMR Laboratory and The Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark

    Birthe B. Kragelund

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Kjaergaard, M., Kragelund, B.B. Functions of intrinsic disorder in transmembrane proteins. Cell. Mol. Life Sci. 74, 3205–3224 (2017). https://doi.org/10.1007/s00018-017-2562-5

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