Skip to ContentSkip to Navigation
Research Zernike (ZIAM) News Seminars

Alessandro Borgia: A new paradigm for biomolecular interactions: ultrahigh-affinity complex of two intrinsically disordered proteins involved in chromatin remodeling

When:Tu 08-05-2018 15:15 - 16:15

In the traditional paradigm of Biology, specificity and affinity are encoded in the precise geometry of complementary shapes at biomolecular interfaces. However, there is mounting evidence that many proteins involved in cellular interactions are unfolded under physiological conditions or contain large unstructured regions. Frequently, these 'intrinsically disordered proteins' (IDPs) still form a well-defined 3D-structure upon binding their target, but parts of the complex often remain unstructured. A broad spectrum of such 'fuzzy' complexes is known, with different degrees of disorder. Recently, indications for protein binding without structure formation have been accumulating, however, it is unclear how much disorder is compatible with high-affinity binding, and how such dynamic protein complexes could be characterized.

We have identified a pair of proteins with key physiological roles that constitute an extreme case of a highly unstructured protein complex. The linker histone H1.0 (H1), is involved in chromatin compaction by binding to nucleosomes and is largely unstructured, with two long tails rich in positively charged residues flanking a small globular domain. The nuclear protein prothymosin α (ProTα), is a fully unstructured acidic IDP also involved in chromatin remodeling and associated with transcription, cellular proliferation, and apoptosis. ProTα has been reported to be a 'linker histone chaperone' in live cells by interacting with H1_ENREF_20 and increasing its mobility in the nucleus_ENREF_21. These human IDPs associate in a complex with picomolar affinity, but they fully retain their disorder, flexibility, and highly dynamic character.

By close integration of single-molecule fluorescence spectroscopy, NMR, and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins and obtain a detailed characterization of this disordered complex, which embodies a new paradigm of biomolecular interactions.