The hidden order of intrinsically disordered proteins and its role in molecular recognition

Borja Mateos
2019 unpublished
Intrinsically disordered proteins (IDPs) exist as an ensemble of rapidly interconverting structures. They do not adopt a stable tertiary structure and explore a large conformational space. However, IDPs differ from denatured proteins in the sense that they probe some energetically favourable compact states. The degree of 'disorder' or compaction is encoded in their primary sequence, which has evolved to provide certain molecular features to carry out specific functions. In particular, the lack
more » ... f a stable structure confers to IDPs an exploratory behaviour, which enables them to participate in a plethora of interaction events. In addition, IDPs provide modularity and adaptability to many biological processes because of their enrichment in post- translational modifications and/or splicing variants. For these reasons, intrinsically disordered regions are generally orchestrating signalling events in eukaryotic cells. In fact, the abnormal behaviour of IDPs is related to cancer and neurodegenerative disorders, among other diseases. In this work, I focus on the metastasis-associated protein Osteopontin (OPN) as an example of a prototypical IDP. OPN is largely disordered with a central compact state that is key to properly orient the interacting motifs of the protein. It is an extracellular protein that interacts with different components of the extracellular matrix (ECM) and two membrane receptor families: integrins and CD44. The aim is to characterize (i) sequence determinants of compaction in IDPs, with particular interest on the effect of prolines; (ii) the evolutionary pressure to conserve particular properties between OPN homologs; (iii) the structural rearrangements upon binding to ECM partners as well as its membrane receptors; (iv) the effect of phosphorylation on the structural dynamics and binding; and (v) the characterization of the disordered regions of CD44 and their binding to OPN. The fast local motions of the polypeptide chain make IDPs exquisitely suited systems to be studied by solution-state nuclear [...]
doi:10.25365/thesis.60692 fatcat:wm6padsfrjffxib55d7n4lws5e