Fig. 6. A working model for the steps in the chaperone-mediated autophagy. Although Hsp90 is present in substoichiometric amounts, we speculate that it may be required for activity of the complex. Step 1: the protein substrate is recognized in the cytosol by the Hsc70 chaperone system. It binds substrates at a KFERQ motif. Step 2: either the substrate binds to the lymHsc70 chaperone system or the cytosolic Hsc70 chaperone system-substrate complex docks at the lysosomal membrane lamp2a. This interaction between Hsc70, substrate, and lamp2a has been previously documented (Cuervo and Dice, 1996). Step 3: the substrate interacts with Lamp2a and is inserted into the translocation complex. Binding of the substrate protein to intralysosomal Hsc70 is required for the substrate protein’s translocation. Step 4: the substrate protein is degraded in the lumen of the lysosome.