New tricks for an old dog: the evolving world of Hsp70.

The Hsp70 chaperone is arguably the most studied member of the heat shock protein family, a legacy traced back to the early days of phage genetics. However, much still remains to be learned about this essential protein-folding machine. Its involvement in a number of human pathologies, ranging from cancer to protein aggregation diseases, underscores the need for a comprehensive understanding of the myriad cellular roles Hsp70 plays and the outstanding open questions. This article will explore several exciting avenues of research into the function and biology of the chaperone. Analysis of the many eukaryotic Hsp70 isoforms has demonstrated distinct functional roles for some Hsp70 members, to the point of transition from a protein "foldase" to a chaperone cofactor. New insights gained from structural studies have unveiled a likely model for interdomain communication and thus regulation of substrate binding and processing. Advances in small molecule modulation of Hsp70 activity are likely to have significant clinical impact. There is also a growing realization that Hsp70 participates in distinct functional networks in partnership with other protein chaperones. The field is thus at an exciting time when the substantial successes of the past have provided a solid framework that will be used to fuel both discovery and application--Hsp70, from molecule to man.