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Extreme Disorder in an Ultra-High-Affinity Protein Complex 2 3 Alessandro Borgia1†*, Madeleine B

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Extreme Disorder in an Ultra-High-Affinity Protein Complex 2 3 Alessandro Borgia1†*, Madeleine B Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2018 Extreme disorder in an ultrahigh-affinity protein complex Borgia, Alessandro ; Borgia, Madeleine B ; Bugge, Katrine ; Kissling, Vera M ; Heidarsson, Pétur O ; Fernandes, Catarina B ; Sottini, Andrea ; Soranno, Andrea ; Buholzer, Karin J ; Nettels, Daniel ; Kragelund, Birthe B ; Best, Robert B ; Schuler, Benjamin Abstract: Molecular communication in biology is mediated by protein interactions. According to the current paradigm, the specificity and affinity required for these interactions are encoded in theprecise complementarity of binding interfaces. Even proteins that are disordered under physiological conditions or that contain large unstructured regions commonly interact with well-structured binding sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction mechanism: the two intrinsically disordered human proteins histone H1 and its nuclear chaperone prothymosin-฀ associate in a complex with picomolar affinity, but fully retain their structural disorder, long-range flexibility and highly dynamic character. On the basis of closely integrated experiments and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins, without requiring defined binding sites or interactions between specific individual residues. Proteome- wide sequence analysis suggests that this interaction mechanism may be abundant in eukaryotes. DOI: https://doi.org/10.1038/nature25762 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-150051 Journal Article Accepted Version Originally published at: Borgia, Alessandro; Borgia, Madeleine B; Bugge, Katrine; Kissling, Vera M; Heidarsson, Pétur O; Fer- nandes, Catarina B; Sottini, Andrea; Soranno, Andrea; Buholzer, Karin J; Nettels, Daniel; Kragelund, Birthe B; Best, Robert B; Schuler, Benjamin (2018). Extreme disorder in an ultrahigh-affinity protein complex. Nature, 555(7694):61-66. DOI: https://doi.org/10.1038/nature25762 1 Extreme disorder in an ultra-high-affinity protein complex 2 3 Alessandro Borgia1†*, Madeleine B. Borgia1†, Katrine Bugge2†, Vera M. Kissling1, Pétur O. Heidarsson1, 4 Catarina B. Fernandes2, Andrea Sottini1, Andrea Soranno1,3, Karin J. Buholzer1, Daniel Nettels1, Birthe B. 5 Kragelund2*, Robert B. Best4*, Benjamin Schuler1,5* 6 7 1Department of Biochemistry, University of Zurich, Zurich, Switzerland 8 2Structural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science and 9 Integrative Structural Biology at University of Copenhagen (ISBUC), Department of Biology, University 10 of Copenhagen, Copenhagen, Denmark 11 3Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. 12 Louis, Missouri, 63110, USA 13 4Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, 14 National Institutes of Health, Bethesda, USA 15 5Department of Physics, University of Zurich, Zurich, Switzerland 16 17 18 †These authors contributed equally to this work 19 *Correspondence should be addressed to B.S. ([email protected]), A.B. ([email protected]), 20 R.B.B. ([email protected]), or B.B.K. ([email protected]) 21 22 23 24 25 Summary 26 Molecular communication in biology is mediated by protein interactions. According to the current 27 paradigm, the specificity and affinity required for these interactions are encoded in the precise 28 complementarity of binding interfaces. Even proteins that are disordered under physiological 29 conditions or contain large unstructured regions commonly interact with well-structured binding 30 sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction 31 mechanism: The two intrinsically disordered human proteins histone H1 and its nuclear chaperone 32 prothymosin α associate in a complex with picomolar affinity, but they fully retain their structural 33 disorder, long-range flexibility, and highly dynamic character. Based on the close integration of 34 experiments and molecular simulations, we show that the interaction can be explained by the large 35 opposite net charge of the two proteins without requiring defined binding sites or interactions 36 between specific individual residues. Proteome-wide sequence analysis suggests that this interaction 37 mechanism may be surprisingly abundant in eukaryotes. 38 1 39 In the conventional paradigm of structural biology, intermolecular interactions are encoded in the 40 complementary shapes and noncovalent forces between folded biomolecules. However, it has become 41 increasingly clear that many proteins involved in cellular interactions are fully or partially unstructured 42 under physiological conditions1,2. In some cases, these intrinsically disordered proteins (IDPs) form a 43 well-defined 3D-structure upon target binding1; in others, parts of the complex remain disordered. A broad 44 spectrum of such protein complexes with different degrees of disorder are known3: Sometimes, a well- 45 defined and structured binding interface is formed in the bound state, and only some loops or the chain 46 termini stay disordered. In other cases, one of the binding partners remains almost completely 47 unstructured in the complex, and its multiple binding motifs dynamically interact with the folded partner. 48 Examples include interdomain interactions in the cystic fibrosis transmembrane regulator4; the cyclin- 49 dependent kinase inhibitor Sic1 binding to the substrate recognition subunit of its ubiquitin ligase subunit 50 Cdc45; the tail of human Na+/H+ exchanger 1 with the extracellular signal-regulated kinase ERK26; or 51 nuclear transport receptors interacting with nucleoporins7. The underlying multivalent binding enables 52 unique regulatory mechanisms8 and can mediate the formation of liquid-liquid phase separation9, 53 indicating the emergence of new modes of biomolecular interactions. 54 We have discovered a pair of proteins that constitutes an extreme case of a highly unstructured 55 protein complex with physiological function. One binding partner, the linker histone H1.0 (H1), which is 56 involved in chromatin condensation by binding to nucleosomes10,11, is largely unstructured12 and highly 57 positively charged, with two disordered regions flanking a small folded globular domain (Fig. 1, Extended 58 Data Table 1). The other partner, the abundant nuclear protein prothymosin α (ProTα), is a fully 59 unstructured, highly negatively charged IDP13,14 involved in chromatin remodeling15, transcription, cellular 60 proliferation, and apoptosis16. ProTα acts as a linker histone chaperone by interacting with H1 and 61 increasing its mobility in the nucleus17. We show here that ProTα and H1 bind to each other with very 62 high affinity, but both proteins fully retain their structural disorder. Based on the integration of 63 complementary experimental techniques and molecular simulations, we obtain a detailed model of this 64 highly disordered and dynamic protein complex, which represents a new paradigm of biomolecular 65 binding. 66 67 A highly unstructured protein complex 68 The binding of H1 to ProTα has been demonstrated both in vitro18 and in vivo17. However, their high net 69 charge, low hydrophobicity, and pronounced disorder in the free proteins raise the question of how much 70 structure is formed when they interact. We used circular dichroism (CD) and nuclear magnetic resonance 71 (NMR) spectroscopy to investigate the formation of secondary and tertiary structure. The CD spectra of 72 unbound ProTα and H1 reflect the low secondary structure content of the individual IDPs, except for the 73 small helix-turn-helix domain of H113,19,20 (Fig. 1c). Surprisingly, the CD spectrum of an equimolar 74 mixture of the two proteins can be explained by the simple sum of the individual spectra, indicating that 75 complex formation entails minimal changes in average secondary structure content. 76 To obtain residue-specific information, we employed NMR spectroscopy. 1H,15N heteronuclear 77 single quantum coherence (HSQC) spectra of the individual proteins exhibit low dispersion of the 1H 78 chemical shifts, as expected for IDPs14,21-23 (Fig. 1e,f). Only the globular domain of H1, which is stably 79 folded even in isolation (Extended Data Fig. 1), shows the large dispersion of resonances characteristic of 80 tertiary structure23,24 (Fig. 1g). Remarkably, the overall peak dispersion remains unchanged upon complex 81 formation, confirming that no pronounced tertiary structure is formed upon binding. Nevertheless, small 82 but clearly detectable peak shifts observed for ProTα and H1 indicate significant changes in the average 83 chemical environment of the corresponding residues, as expected upon interaction with the large opposite 84 charge of the other IDP. For ProTα, 95% of the amide backbone nuclei could be assigned (Extended Data 85 Fig. 2), enabling a residue-specific analysis: The Cα secondary chemical shifts25 of ProTα show no 86 evidence for the induction of persistent or transiently populated secondary structure upon complex 87 formation (Fig. 1d). The severe overlap in the NMR spectra of the unstructured parts of H1 precluded 88 residue-specific assignments, but the clusters of Hα-Cα peaks in the 1H,13C-HSQC spectrum from the 89 lysine-rich disordered regions neither exhibit detectable chemical shift perturbations upon titration
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