Twenty years with Intrinsically Disordered (“Unstructured”) Proteins
Prof. Kyou-Hoon Han, Distinguished Research Fellow, Korea Research Institute of Bioscience and Biotechnology
Intrinsically Disordered Proteins (IDPs) are highly unorthodox proteins that do not form three-dimensional structures under physiological conditions. Discovery of IDPs has destroyed the classical structure-function paradigm in protein science, 3-D structure = function, because IDPs even without well-folded 3-D structures are still capable of performing important biological functions and furthermore are associated with fatal diseases such as cancers, neurodegenerative diseases and viral pandemics. Starting with the transcriptional activation domain of the tumor-suppressor p53 my laboratory has been paving a way for the last two decades to understand the structural features of IDPs in order to understand how malleable IDPs, without any spatially-disposed active pockets, would bind targets to manifest their function. The structural rationale for IDP-target binding we have been proposing is so-called the pre-structured motifs (PreSMos) concept. PreSMos are local secondary structural elements populated transiently (typically ~30%) in the target-free IDPs presence of which is reflected in several independent NMR parameters. The PreSMo concept is a relatively new hypothesis that contrasts to the early-day notion that IDPs are completely unstructured down to the level of secondary structures and need to undergo a coil-> helix type full induced fit transition for target binding.
1. Salamanova, E., Costeira-Paulo, J., Han, K. H., Kim, D. H., Nilsson, L., Wright, A. P. H. (2018) A subset of functional adaptation mutations alter propensity for a-helical conformation in the intrinsically disordered glucocorticoid receptor tau1core activation domain. BBA - General Subjects, 1862, 1452–1461
2. Kim, D. H., Lee, C., Lee, S. H., Kim, K. T., Han, J. J., Cha, E. J., Lim, J. E., Cho, Y. J,, Hong, S. H., Han, K. H. (2017) The Mechanism of p53 Rescue by SUSP4. Angew. Chem. Int. Ed., 56, 1278 –1282
3. Tompa, P., Han, K. H., Bokor, M., Kamasa, P., Tantos, Á., Fritz, B., Kim, D. H., Lee, C., Verebélyi, T., Tompa, K. (2016) Wide-line NMR and DSC studies on intrinsically disordered p53 transactivation domain and its helically prestructured segment. BMB Rep., 49, 497-501
4. Kim, D. H., Lee, C., Cho, Y. J., Lee, S. H., Cha, E. J., Lim, J. E., Sabo, T. M., Griesinger, C., Lee, D., Han, K. H. (2015) A pre-structured helix in the intrinsically disordered 4EBP1. Mol. BioSyst., 11, 366-369 (hot article of year)
5. Lee, C., Kalmar, L., Xue, B., Tompa, P., Daughdrill, G. W., Uversky, V. N., Han, K. H. (2014) Contribution of proline to the pre-structuring tendency of transient helical secondary structure elements in intrinsically disordered proteins. BBA - General Subjects, 1840, 993–1003
6. S.H. Lee, D.H. Kim, J.J. Han, E.J. Cha, J.E. Lim, Y.J. Cho, C. Lee, K.H. Han (2012) Understanding pre-structured motifs (PreSMos) in intrinsically unfolded proteins, Curr. Protein Pept. Sci., 13, 34–54.
Monday, May 7 at 11:00am
Regents Hall, 451
3700 O St. NW