Intrinsically unstructured proteins and neurodegenerative diseases: conformational promiscuity at its best

Neurodegenerative diseases are complex, multifactorial disorders where misfolding of proteins cause aberrant protein-protein interactions. They are not usually characterized by specific mutations especially for nonfamilial disease types. Most of the causative proteins, however, are intrinsically unstructured (IUP), loss of whose fine balance could play pivotal role in these processes. Very fast conformational switch of these IUPs between different functional forms, so as to choose different interaction partners and different functional niches within the cell, is the basic premise on which these proteins maintain their interaction network. We are working on the hypothesis that even small perturbations in conformation leads to disruption of the network and to the disease phenotype. Based on a comprehensive data search, the evidence was obtained for the role of IUPs in neurodegenerative disorders, and their mode of action through conformational promiscuity is elaborated through three case studies.