Protein folding and the order/disorder paradox

Prakash Kulkarni, Krithika Rajagopalan, David Yeater, Robert H. Getzenberg

Research output: Contribution to journalArticlepeer-review


Most proteins encoded by the nuclear genome are synthesized in the cytoplasm and fold into precise 3D structures. During synthesis, the nascent polypeptide begins to fold as it traverses the large subunit of the ribosome and is assisted by molecular chaperones in attaining its precise folded/highly ordered state efficiently and in a biologically relevant timescale. Proteins that are misfolded are culled, re-routed, and marked by mechanisms such as ubiquitinylation for degradation ensuring strict quality control (QC). In addition to the highly ordered ''globular'' proteins, emerging evidence indicates that a large fraction of the proteome also comprises the so-called ''Intrinsically Disordered Proteins'' (IDPs). IDPs are proteins that lack rigid 3D structures and instead, exist as dynamic ensembles. The dynamic structures in the IDPs have many similarities with ''normal'' globular proteins such as the native (ordered), and non-native (molten globule, pre-molten globule, and coil-like) states seen during folding of ''normal'' globular proteins. However, unlike the case of the nascent globular proteins, IDPs evade being detected as ''misfolded'' and degraded by the cell's QC system. We refer to this paradox as the order/disorder paradox and postulate that the IDPs capitalize on their intrinsic promiscuity and ability to undergo disorder-to-order transitions upon binding to biological targets (coupled folding and binding) to escape the cell's surveillance machinery. Understanding the mechanism by which the IDPs evade the quality check has wide implications from protein folding to disease biology since the aggregation of misfolded proteins underlies several debilitating illnesses such as many neurodegenerative diseases and cancer.

Original languageEnglish (US)
Pages (from-to)1949-1952
Number of pages4
JournalJournal of cellular biochemistry
Issue number7
StatePublished - Jul 2011


  • Cancer
  • Cancer/testis antigens
  • Order/disorder paradox
  • Proteasome
  • Protein folding

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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