Heat Shock Proteins (HSPs): Structure, Function and Genetics


Heat shock proteins are evolutionarily well‐conserved, ATP‐binding proteins that function as molecular chaperones in facilitating protein folding and degradation. They are expressed constitutively in various cell types, but the expression of certain family members is strongly induced in response to stress stimuli.

Keywords: heat shock proteins; chaperones; protein folding; protein degradation; heat shock genes

Figure 1.

Hsp70 domains. The 44‐kDa, N‐terminal ATPase domain and the 15‐kDa substrate‐binding domain are highly conserved among the Hsp70s from various species. G/P denotes a region rich in glycine and proline residues. Numbers from 1 to 641 indicate the amino acids.

Figure 2.

Hsp90 chaperone cycle in steroid hormone receptor (SHR) activation. The ligand‐free SHR is bound by Hsp70 in a reaction requiring ATP hydrolysis and the cochaperone Hsp40. Two additional Hsp70‐binding cochaperones, the Hsp70‐interacting protein Hip and BAG‐1, have been identified in receptor complexes but are nonessential in minimal in vitro hormone‐binding assays. Binding of Hop (Hsp70/Hsp90 organizing protein) to this complex leads to the formation of the early complex and, consequently, the Hsp90 dimer is recruited via Hop in an ATP‐dependent reaction. Geldanamycin (GA), a naturally occurring benzoquinone ansamycin, and other specific inhibitors bind to Hsp90, disrupting the complex between Hsp90 and the client, thereby promoting proteolytic degradation of the substrate. Hsp70, its cochaperones and Hop are exchanged from the intermediate complex for one of the large immunophilins (IP) and the p23 chaperone to yield the mature complex. The SHR is spontaneously released from this complex and is able to bind hormone, to dimerize and to bind DNA. Alternatively, the SHR reenters the cycle in the absence of hormone, which ensures that the SHR remains in an inactive state. Modified from Richter and Buchner .

Figure 3.

Structure of the human Hsp70‐1 promoter. Transcription of the human hsp70‐1 gene is regulated through multiple promoter elements that differentially mediate the basal and stress‐inducible expression. The basal expression is mediated by a compact, multicomponent array of proximal and distal promoter elements, represented by CCAAT, GC and TATA boxes (binding sites for transcription factors CTF, Sp1 and TBP, respectively). The stress‐inducible increase in transcription of the human hsp70‐1 gene is mediated via heat shock elements (HSEs), the number and architecture of which vary depending on the heat shock gene promoter. A functional HSE is composed of at least three inverted pentameric sequences NGAAN, serving as a binding site for the specific heat shock transcription factors (HSFs). The promoter of the strictly heat‐inducible Hsp70B′ lacks TATA and CCAAT boxes, which contribute to the basal expression of Hsp70‐1. The hsp70‐HOM gene, in contrast, contains neither an HSE nor a CCAAT box in its 5′ flanking region.

Figure 4.

Inducible transcription of heat shock genes. Upon stress stimuli, HSF1 undergoes several posttranslational modifications: it is oligomerized from an inactive monomer to an active trimer via hydrophobic heptad repeats, concentrates to the nucleus, becomes phosphorylated, and binds to the Hsp70‐1 promoter (the HSFs have a helix‐‐turn‐‐helix DNA‐binding domain), thereby activating Hsp70‐1 transcription. The inducible phosphorylation is essential for the transcriptional competence of HSF1. During recovery from stress, HSF1 activity is repressed by the accumulated hsp70 and certain assisting proteins, and HSF1 is released from DNA and converted to the monomeric form. Hsp90 is critical in keeping HSF1 in the inactive form.



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Further Reading

Alastalo T‐P, Rallu M, Gitton Y, et al. (2002) Brain abnormalities, defective meiotic chromosome synapsis and female subfertility in HSF2 null mice. EMBO Journal 21: 2591–2601.

Bettencourt BR and Feder ME (2001) Hsp70 duplication in the Drosophila melanogaster species group: how and when did two become five? Molecular Biology and Evolution 18: 1272–1282.

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Web Links

Heatshock 70 kDa protein 1A (HSPA1A); LocusID: 3303. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=3303

Heatshock 70 kDa protein 1B (HSPA1B); LocusID: 3304. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=3304

Heatshock 70 kDa protein 1‐like (HSPA1L); LocusID: 3305. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=3305

Heatshock 90 kDa protein 1, α‐like 3 (HSPCAL3); LocusID: 3324. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=3324

Heatshock 90 kDa protein 1, β (HSPCB); LocusID: 3326. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=s3326

Heatshock 70 kDa protein 1A (HSPA1A); MIM number: 140550. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?140550

Heatshock 70 kDa protein 1B (HSPA1B); MIM number: 603012. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?603012

Heatshock 70 kDa protein 1‐like (HSPA1L); MIM number: 140559. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?140559

Heatshock 90 kDa protein 1, α‐like 3 (HSPCAL3); MIM number: 140575. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?140575

Heatshock 90 kDa protein 1, β (HSPCB); MIM number: 140572. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?140572

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Pirkkala, Lila, and Sistonen, Lea(Jan 2006) Heat Shock Proteins (HSPs): Structure, Function and Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0006130]