The human HSP70 family comprises at least eight unique gene products that differ from each other by amino acid sequence, expression level and sub-cellular localization (Daugaard M et al. 2007). HSP70 family members display highly conserved amino acid sequences and domain structures consisting of: the ATPase N-terminal domain that binds and hydrolyzes ATP (NBD), the substrate domain (SBD) that binds to exposed hydrophobic segments of client polypeptides and promote their solubility and/or folding in a dynamic ATP-dependent manner, and the C-domain that provides a “lid” for the substrate domain (Zhang P et al. 2014; Brocchieri L et al. 2008; Wisniewska M et al. 2010). The conserved domain structure consolidates the chaperone function of the Hsp70 proteins and enables them to bind and release extended stretches of hydrophobic amino acids, exposed by incorrectly folded globular proteins in an ATP-dependent manner (Takayama S et al. 1999; Mayer MP 2013; Daugaard M et al. 2007). The initial binding of an unfolded client protein by a heat shock protein 40 (HSP40) prevents its aggregation and 'delivers' it to HSP70. The substrate binding ability of HSP70 is dependent on its bound state to either ATP or ADP (Kityk R et al. 2012; Qi R et al. 2013). Client substrates enter the HSP70 functional cycle by binding the ATP form of the chaperone, which has lower substrate affinity but faster binding and release rates compared with the ADP state. Interaction of the client in the cleft results in conformational changes in NBD that modestly increase ATP hydrolysis. Second, a transient interaction of HSP70 with J-protein co-chaperone HSP40, which has a higher affinity to ATP-bound HSP70 than ADP-bound HSP70, also stimulates the ATPase activity of HSP70 (Wittung-Stafshede P et al. 2003).