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

Document Type


Publication Date



Intrinsically disordered regions, Transmembrane proteins, Integrative modelling, Protein design

Digital Object Identifier (DOI)


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.

Was this content written or created while at USF?


Citation / Publisher Attribution

The Journal of Membrane Biology, v. 252, p. 273-292