ATLAS and Functional Genomics and Metabolism
Joint Distinguished Seminar
Friday, February 1 from 11-12
in BMB Seminar room
Intrinsically disordered proteins and regions
– why bother?
by Prof. Birthe B. Kragelund
Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Denmark
Abstract
Intrinsically disordered proteins (IDPs) (or –regions (IDRs)) are functional while existing in broad ensembles of near iso-energetic conformations. Despite their lack of tertiary structure, IDPs are involved in communication with other molecules forming associations ranging from binary, discrete complexes to large multicomponent assemblies. Similar to globular proteins their complexes serve structural, functional and regulatory roles, but due to their dynamic nature, they expand the types of association possible, further enabling functional regulations by very different mechanisms. The fast dynamics characteristic of IDPs may persist in their complexes and the degrees of disorder within the complex can therefore vary greatly. We have been exploring the role of disorder in cellular control processes including pH homeostasis, cytokine signalling, transcriptional regulation, and DNA metabolism, combining NMR spectroscopy with other biophysical methods as SAXS, neutron diffraction, single-molecule FRET and cell biology [1–4]. In one end of the scale we observe folding-upon-binding forming nearly globular-like complexes with little disorder while at the other end, disorder may persist and results in complexes where both binding partners stay disordered despite high-affinity binding [3]. Still, the kinetics combined with higher order complex formation allows regulation on biologically relevant timescales. Between these extremes, a continuum of dynamic complexes is possible. The characterisation and functional decoding of dynamic complexes challenges the methodological toolbox, but NMR spectroscopy continues to be a critical contributor in the understanding of disorder dependent biology.
1 Bugge, K., Papaleo, E., Haxholm, G. W., Hopper, J. T. S., Robinson, C. V., Olsen, J. G., Lindorff-Larsen, K. and Kragelund, B. B. (2016) A combined computational and structural model of the full-length human prolactin receptor. Nat. Commun. 7, 11578.
2 Bugge, K., Staby, L., Kemplen, K. R., O’Shea, C., Bendsen, S. K., Jensen, M. K., Olsen, J. G., Skriver, K. and Kragelund, B. B. (2018) Structure of Radical-Induced Cell Death1 Hub Domain Reveals a Common αα-Scaffold for Disorder in Transcriptional Networks. Structure 26, 734–746.e7.
3 Borgia, A., Borgia, M. B., Bugge, K., Kissling, V. M., Heidarsson, P. O., Fernandes, C. B., Sottini, A., Soranno, A., Buholzer, K. J., Nettels, D., et al. (2018) Extreme disorder in an ultrahigh-affinity protein complex. Nature, 555, 61–66.
4 Hendus-Altenburger, R., Pedraz-Cuesta, E., Olesen, C. W., Papaleo, E., Schnell, J. A., Hopper, J. T. S., Robinson, C. V, Pedersen, S. F. and Kragelund, B. B. (2016) The human Na(+)/H(+) exchanger 1 is a membrane scaffold protein for extracellular signal-regulated kinase 2. BMC Biol., 14, 31.
Host: Prof. Susanne Mandrup, Functional Genomics & Metabolism Research Unit, Dept. Biochemistry and Molecular Biology, SDU