The Cross-Border Biotech Blog

Biotechnology, Health and Business in Canada, the United States and Worldwide

Friday Science Review: April 13, 2012

Intrinsically disordered proteins, i.e. proteins or regions of proteins that do not adopt defined structural folds, but rather exist as a dynamic ensemble of structures, are a fascinating and important area of biology. Members of this class of proteins are enriched in cell signaling, transcription and translation, where their lack of fixed structure must be conferring a functional advantage.  Often involved in multiple interactions and subject to complex control through post-translational modification, these proteins have immense biomedical relevance, however, their very nature and complexity complicates attempts to characterize them.

Results reported in PNAS by researchers from the Ontario Cancer Institute are gradually filling in the details for one such protein, FOXO3a. This ubiquitously expressed protein activates transcription of genes responsible for differentiation, DNA repair, cell cycle regulation, stress resistance and apoptosis, which it achieves by binding to specific elements in DNA, followed by recruitment of the coactivator CBP/p300. Using nmr on peptides from the intrinsically disordered region of FOXO3a in the presence of the cognate binding partner domain from CBP/p300, they confirmed that two regions of FOXO3a are involved in the interaction, but unexpectedly that the complex is dynamic and exists in two conformationally distinct states. Furthermore, recruitment of CBP/p300 is promoted by interactions with other domains of CBP/p300 and the interaction can be further enhanced by phosphorylation at a specific position within the disordered CBP/p300 binding region of FOXO3a.

These findings help to build a model of the dynamic, promiscuous and multivalent interactions that underlie the functions of intrinsically disordered proteins and can help us to understand why an intrinsic lack of structure can have advantages in both recruiting binding partners and providing mechanisms to modulate those interactions.

Other Publications:

  • Critical Evaluation of Imprinted Gene Expression by RNA-Seq: A New Perspective. PLoS Genetics. University of Toronto
  • Blockade of Fatty Acid synthase triggers significant apoptosis in mantle cell lymphoma. PLoS One. University of Alberta and Cross Cancer Institute
  • EGF-Induced EMT and Invasiveness in Serous Borderline Ovarian Tumor Cells: A Possible Step in the Transition to Low-Grade Serous Carcinoma Cells? PLoS One. University of British Columbia
  • Real-time visualization and quantitation of vascular permeability in vivo: implications for drug delivery. PLoS One. Innovascreen, Inc.
  • Lentivector Transduction Improves Outcomes Over Transplantation of Human HSCs Alone in NOD/SCID/Fabry Mice. Molecular Therapy. University Health Network, Toronto
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