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8 Interactions of Vertebrate hsc70 and hsp70 with Unfolded Proteins and Peptides

Lawrence E. Hightower, Seth E. Sadis, Ivone M. Takenaka


This chapter is the companion to McKay’s chapter in this volume on the ATP-binding domain of the vertebrate hsp70 protein family. We have attempted to pull together what is known about the interactions of the carboxy-terminal domains of vertebrate hsc70 and hsp70 with unfolded proteins and peptides and about the interactions between the peptide-binding and ATPase domains. The molecular structure of the crystallized ATP-binding domain has been determined by X-ray diffraction (Flaherty et al. 1990); however, the three-dimensional structure of the peptide-binding domain is not known. Therefore, computerized structural predictions have been used to model the carboxy-terminal domain.

Because of the manner in which information on the functions of this protein family was initially developed, primarily through serendipitous discoveries of roles in normal cellular processes, much more is known about the constitutive or cognate members such as hsc70 than the stress-inducible members (hsp70). Thus, evidence of “molecular chaperone” functions comes primarily from studies of the cognates. Molecular chaperones are proteins that facilitate the folding or assembly and disassembly of other proteins but are not part of the finished structure (for recent reviews, see Ang et al. 1991; Craig et al. 1993; Georgopoulos and Welch 1993; Hendrick and Hartl 1993). The current hypotheses regarding chaperoning mechanisms for the hsp70 family include (1) binding to nascent polypeptides to delay folding until synthesis of the polypeptide chain is completed and all of the information needed for folding is present, (2) delaying folding until the polypeptide reaches the appropriate cellular compartment, (3)...

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