Non-folding signals and their decoding by chaperones in the secretory pathway

Non-Fold explores the hypothesis that secretory proteins have evolved unique structural/sequence characteristics that set them apart as a novel and unique structural class. (Pre)secretome polypeptides have a strong inherent propensity for elevated disorder and flexibility, These properties maintain secretory chains in stable kinetic, non-folding, and yet commonly soluble, traps with three major repercussions: a. they facilitate polypeptide membrane targeting and crossing b. they facilitate exposure of sub-cellular location signals (e.g.to reach translocases) and c. once translocated they need assistance to fold in the cell envelope and beyond. Understanding the principle components of these properties is not only of fundamental to our understanding protein secretion, an essential cellular process, but also directly impinges on how all polypeptides acquire/maintain folded states and avoid aggregation. Non-Fold will advance our understanding of what internal/external features evolved to allow secretory proteins to remain in various states of non-foldedness during synthesis, while they travel to membranes and after crossing them. Moreover, it will reveal how signal peptides, N-terminal rheostats, internal MTSs and other elements of the sequence co-ordinate to bring about non-foldedness in secretory proteins. Also, how these are recognized by chaperones and have 'holding' or 'folding' repercussions.