Protein solubility and folding monitored in vivo by structural complementation of a genetic marker protein

Protein misfolding is the basis of a number of human diseases and presents an obstacle to the production of soluble recombinant proteins. We present a general method to assess the solubility and folding of proteins in vivo. T he basis of this assay is structural complementation between the alpha- and omega -fragments of beta -galactosidase (beta -gal). Fusions of the alpha -fragment to the C terminus of target proteins with widely varying in vivo folding yield and/or solubility levels, including the Alzheimer's amyloid b eta (A beta) peptide and a non-amyloidogenic mutant thereof, reveal an unam biguous correlation between beta -gal activity and the solubility/folding o f the target. Thus, structural complementation provides a means of monitori ng protein solubility/misfolding in vivo, and should find utility in the sc reening for compounds that influence the pathological consequences of these processes.