Molecular Insight into the Extracellular Chaperone Serum Albuminin Modifying the Folding Free Energy Landscape of Client Proteins br

Serum albumin (SA) is the most abundant extracellular chaperone proteinpresenting in various bodilyfluids. Recently, several studies have revealed molecularmechanisms of SA in preventing the amyloid formation of amyloidogenic proteins. However,our insight into the mechanism SA employed to sense and regulate the folding states of full-length native proteins is still limited. Addressing this question is technically challenging dueto the intrinsic dynamic nature of both chaperones and clients. Here using nuclear magneticresonance spectroscopy, we show SA modifies the folding free energy landscape of clients andsubsequently alters the equilibria between different compact conformations of its clients,resulting in the increased populations of excited states of client proteins. This modulation ofclient protein conformation by SA can change the client protein activity in a way that cannotbe interpreted on the basis of its ground state structure; therefore, our work provides analternative insight of SA in retaining a balanced functional proteome.