COFACTOR-INDUCED MODULATION OF THE FUNCTIONAL SPECIFICITY OF THE MOLECULAR CHAPERONE HSC70

Molecular chaperones differ in their ability to stabilize nonnative po lypeptides and to mediate protein folding, defining 'holding' and 'fol ding' systems, Here we show that the mammalian cytosolic and nuclear c haperone Hsc70 can act as both, as a 'holding' and a 'folding' system, depending on the chaperone cofactors which associate with Hsc70. In c onjunction with the cofactor Hsp49, Hsc70 stabilizes heat-denatured fi refly luciferase. The stabilizing activity turns into a folding activi ty in the additional presence of the Hsc70-interacting protein Hip. In contrast, the cofactor BAG-1 abrogates the 'holding' function of the Hsc70/Hsp40 system and blocks the action of Hip on Hsc70. Our study sh eds light on the molecular mechanisms that determine the functional sp ecificity of Hsc70 in the mammalian cell.