Proteins are the molecules of life. Many of them fulfill their functions in living organisms only if they take on a very well-defined shape, such that they are able to work like little machines. This is for example the case for enzymes that catalyze biochemical reactions. However, there is a large number of proteins that are not folded but intrinsically disordered. These proteins can fold into well-defined structures when they bind to their target, but in some cases they even remain disordered when they bind to other molecules. Furthermore, such intrinsically disordered proteins (IDPs) can often undergo a very wide range of different processes, some of which are functional and some of which are deleterious. Examples include the association into highly concentrated liquid-like droplets, so-called condensates, or into highly ordered fibrillar structures, so-called amyloid fibrils. The latter assemblies are hallmarks of a range of severe disorders, such as Alzheimer's and Parkinson's diseases. It is becoming increasingly clear that despite the lack of a clear structure in their native state, small changes in the amino acid sequence of an IDP can have dramatic consequences on its interactions and assembly behavior. In the EMMA project, our aim is to develop a range of new methods to study the effects of changes in amino acid sequence more widely and efficiently than has been possible until now. Notably, a systematic variation of the protein sequence for quantitative biophysical studies requires an enormous number of sequence variants to be studied. That is why new methods at higher throughput and that are automatable are required for such studies. In EMMA, we will develop further and apply our new methods to the study of the proteins alpha-synuclein and a fragment of TDP-43. The choice of these protein systems is motivated through the observation that the assembly, condensate formation and aggregation of these proteins are linked to the diseases Parkinson's and amyotrophic lateral sclerosis, respectively.
