Disorder and cysteines in proteins: A design for orchestration of conformational see-saw and modulatory functions

Anukool A. Bhopatkar, Vladimir N. Uversky, Vijayaraghavan Rangachari

Research output: Chapter in Book/Report/Conference proceedingChapter

20 Scopus citations

Abstract

Being responsible for more than 90% of cellular functions, protein molecules are workhorses in all the life forms. In order to cater for such a high demand, proteins have evolved to adopt diverse structures that allow them to perform myriad of functions. Beginning with the genetically directed amino acid sequence, the classical understanding of protein function involves adoption of hierarchically complex yet ordered structures. However, advances made over the last two decades have revealed that inasmuch as 50% of eukaryotic proteome exists as partially or fully disordered structures. Significance of such intrinsically disordered proteins (IDPs) is further realized from their ability to exhibit multifunctionality, a feature attributable to their conformational plasticity. Among the coded amino acids, cysteines are considered to be “order-promoting” due to their ability to form inter- or intramolecular disulfide bonds, which confer robust thermal stability to the protein structure in oxidizing conditions. The co-existence of order-promoting cysteines with disorder-promoting sequences seems counter-intuitive yet many proteins have evolved to contain such sequences. In this chapter, we review some of the known cysteine-containing protein domains categorized based on the number of cysteines they possess. We show that many protein domains contain disordered sequences interspersed with cysteines. We show that a positive correlation exists between the degree of cysteines and disorder within the sequences that flank them. Furthermore, based on the computational platform, IUPred2A, we show that cysteine-rich sequences display significant disorder in the reduced but not the oxidized form, increasing the potential for such sequences to function in a redox-sensitive manner. Overall, this chapter provides insights into an exquisite evolutionary design wherein disordered sequences with interspersed cysteines enable potential modulatory protein functions under stress and environmental conditions, which thus far remained largely inconspicuous.

Original languageEnglish (US)
Title of host publicationDancing Protein Clouds
Subtitle of host publicationIntrinsically Disordered Proteins in Health and Disease, Part B
EditorsVladimir N. Uversky, Vladimir N. Uversky
PublisherElsevier B.V.
Pages331-373
Number of pages43
ISBN (Print)9780128226155
DOIs
StatePublished - 2020
Externally publishedYes

Publication series

NameProgress in Molecular Biology and Translational Science
Volume174
ISSN (Print)1877-1173
ISSN (Electronic)1878-0814

Keywords

  • Cysteine-rich sequences
  • Cysteines
  • Disulfide bonds
  • Intrinsically disordered proteins
  • Intrinsically disordered regions
  • Metal binding
  • Modulatory functions
  • Redox sensitivity

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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