The Journal of Membrane Biology

, Volume 252, Issue 4–5, pp 273–292 | Cite as

The Structural and Functional Diversity of Intrinsically Disordered Regions in Transmembrane Proteins

  • Rajeswari Appadurai
  • Vladimir N. Uversky
  • Anand SrivastavaEmail author
Part of the following topical collections:
  1. Membrane and Receptor Dynamics


The intrinsically disordered proteins and protein regions (IDPs/IDPRs) do not have unique structures, but are known to be functionally important and their conformational flexibility and structural plasticity have engendered a paradigmatic shift in the classical sequence–structure–function maxim. Fundamental understanding in this field has significantly evolved since the discovery of this class of proteins about 25 years ago. Though the IDPRs of transmembrane proteins (TMP-IDPRs) comply with the broad definition of typical IDPs and IDPRs found in water-soluble globular proteins, much less is explored and known about them. In this review, we assimilate the key emerging biophysical principles from the limited studies on TMP-IDPRs and provide several context-specific biological examples to highlight the ubiquitous nature of TMP-IDPRs and their functional importance in cellular functions. Besides providing a spectrum of insights from sequence to structural disorder and functions, we also review the challenges and methodological advances in studying the structure–function relationship of TMP-IDPRs. We also lay stress upon the importance of an integrative framework, where ensemble-averaged (and mostly low-resolution) data from multiple experiments can be faithfully integrated with modelling techniques such as advanced sampling, coarse-graining, and free energy minimization methods for a high-fidelity characterization of TMP-IDPRs. We close the review by providing futuristic perspective with suggestions on how we could use the ideas and methods from the exciting field of protein engineering in conjunction with integrative modelling framework to advance the IDPR field and harness the sequence–disorder–function paradigm towards functional design of proteins.


Intrinsically disordered regions Transmembrane proteins Integrative modelling Protein design 



R.A. and A.S. would like to thank Krishnakanth Baratam for discussions and insights on integrative structural modelling aspects of IDPRs. A.S. thanks the funding from the Ministry of Human Resource Development of India and the early career grant from the Department of Science and Technology of India (DST-India). R.A. thanks the DST-India for her national postdoctoral fellowship. This research is also supported by the Department of Biotechnology, Government of India in the form of IISc-DBT partnership programme. Support from FIST program sponsored by the Department of Science and Technology and UGC, India – Centre for Advanced Studies and Ministry of Human Resource Development, India is gratefully acknowledged.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflicts of interest with the contents of this article.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Molecular Biophysics Unit, Biological Sciences DivisionIndian Institute of ScienceBangaloreIndia
  2. 2.Department of Molecular Medicine and Byrd Alzheimer’s Research Institute, Morsani College of MedicineUniversity of South FloridaTampaUSA
  3. 3.Protein Research GroupInstitute for Biological Instrumentation of the Russian Academy of SciencesPushchinoRussia

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