Cryptic epitopes and functional diversity in extracellular proteins

The functional diversity of proteins is a major factor determining the complexity of cells and tissues. Both translational and post-translational modifications contribute to this diversity. Recently, protein unfolding and refolding has been recognised as another mechanism for diversity by unmasking buried or cryptic sequences (epitopes) that possess physiological functions. In the current review, we focus on extracellular proteins where folding dynamics can be influenced by mechanical forces, protein-protein interactions and denaturation. Many cryptic epitopes in these proteins are exposed following proteolytic cleavage, but recent data indicate that unfolding/refolding play an important role in regulating the physiological behaviour of extracellular proteins. By understanding how and when hidden sequences are exposed, novel techniques for manipulating the function of these proteins may be uncovered.