1Molecular Chaperones and the Ubiquitin–

A role for the ubiquitin–proteasome system in the removal of misfolded and ab-normal proteins is well established. Nevertheless, very little is known about how abnormal proteins are recognized for degradation by the proteasome. Recent ad-vances suggest that substrate recognition and processing require a close coopera-tion of the ubiquitin–proteasome system with molecular chaperones. Chaperones are defined by their ability to recognize nonnative conformations of other proteins and are therefore ideally suited to distinguish between native and abnormal pro-teins during substrate selection. Here we discuss molecular mechanisms that underlie the cooperation of molecular chaperones with the ubiquitin–proteasome system. Advancing our knowledge about such mechanisms may open up opportu-nities to modulate chaperone–proteasome cooperation in human diseases. 1.