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The 70 kilodalton heat shock proteins (Hsp70s) are a family of ubiquitously expressed proteins. Proteins with similar structure exist in virtually all living organisms. The Hsp70s are an important part of the cell's machinery for protein folding, and help to protect cells from stress.
Additional recommended knowledge
Members of the Hsp70 family are strongly upregulated by heat stress and toxic chemicals, particularly heavy metals such as arsenic, cadmium, copper, mercury, etc. Hsp70 was originally discovered by FM Ritossa in the 1960s when a lab worker accidentally boosted the incubation temperature of Drosophila (fruit flies). When examining the chromosomes, Ritossa found a "puffing pattern" that indicated the elevated gene transcription of an unknown protein. This was later described as the "Heat Shock Response" and the proteins were termed the "Heat Shock Proteins" (Hsps).
All of the Hsp70 proteins have three major functional domains.
Function and regulation
When not interacting with a substrate peptide, Hsp70 is usually in an ATP bound state. Hsp70 by itself is characterized by a very weak ATPase activity, such that spontaneous hydrolysis will not occur for many minutes.
As newly synthesized proteins emerge from the ribosomes, the substrate binding domain of Hsp70 recognizes sequences of hydrophobic amino acid residues, and interacts with them. This spontaneous interaction is reversible, and in the ATP bound state Hsp70 may relatively freely bind and release peptides.
However, the presence of a peptide in the binding domain stimulates the ATPase activity of Hsp70, increasing its normally-slow rate of ATP hydrolysis. When ATP is hydrolyzed to ADP the binding pocket of Hsp70 closes, tightly binding the now-trapped peptide chain. Further speeding ATP hydrolysis are the so-called J-domain cochaperones: primarily Hsp40 in eukaryotes, and DnaJ in prokaryotes. These cochaperones dramatically increase the ATPase activity of Hsp70 in the presence of interacting peptides.
By binding tightly to partially-synthesized peptide sequences (incomplete proteins), Hsp70 prevents them from aggregating and being rendered nonfunctional. Once the entire protein is synthesized, a nucleotide exchange factor (BAG-1 and HspBP1 are among those which have been identified) stimulates the release of ADP and binding of fresh ATP, opening the binding pocket. The protein is then free to fold on its own, or to be transferred to other chaperones for further processing. HOP (the H'sp70/Hsp90 Organizing Protein) can bind to both Hsp70 and Hsp90 at the same time, and mediates the transfer of peptides from Hsp70 to Hsp90.
Hsp70 also aids in transmembrane transport of proteins, by stabilizing them in a partially-folded state.
Hsp70 proteins can act to protect cells from thermal or oxidative stress. These stresses normally act to damage proteins, causing partial unfolding and possible aggregation. By temporarily binding to hydrophobic residues exposed by stress, Hsp70 prevents these partially-denatured proteins from aggregating, and allows them to refold.
Finally, Hsp70 seems to be able to participate in disposal of damaged or defective proteins. Interaction with CHIP (Carboxyl-terminus of Hsp70 Interacting Protein)–an E3 ubiquitin ligase–allows Hsp70 to pass proteins to the cell's ubiquitination and proteolysis pathways.
HSP 70 is overexpressed in malignant melanoma and in renal cell cancer.
Eukaryotic organisms express several slightly different Hsp70 proteins. All share the common domain structure, but each has a unique pattern of expression or subcellular localization.
Prokaryotes express three Hsp70 proteins: DnaK,HscA (Hsc66), HscC (Hsc62).
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Hsp70". A list of authors is available in Wikipedia.