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Regulation of Signaling Protein Function and Trafficking by the hsp90/hsp70-Based Chaperone Machinery
- Source :
- Experimental Biology and Medicine. 228:111-133
- Publication Year :
- 2003
- Publisher :
- SAGE Publications, 2003.
-
Abstract
- Nearly 100 proteins are known to be regulated by hsp90. Most of these substrates or “client proteins” are involved in signal transduction, and they are brought into complex with hsp90 by a multlprotein hsp90/hsp70-based chaperone machinery. In addition to binding substrate proteins at the chaperone site(s), hsp90 binds cofactors at other sites that are part of the heterocomplex assembly machinery as well as immunophllins that connect assembled substrate·hsp90 complexes to protein-trafficking systems. In the 5 years since we last reviewed this subject, much has been learned about hsp90 structure, nucleotide-binding, and cochaperone interactions; the most important concept is that ATP hydrolysis by an intrinsic ATPase activity results in a conformational change in hsp90 that is required to induce conformational change in a substrate protein. The conformational change induced in steroid receptors is an opening of the steroid-binding cleft so that it can be accessed by steroid. We have now developed a minimal system of five purified proteins—hsp90, hsp70, Hop, hsp40, and p23—that assembles stable receptor·hsp90 heterocomplexes. An hsp90·Hop·hsp70·hsp40 complex opens the cleft in an ATP-dependent process to produce a receptor·hsp90 heterocomplex with hsp90 in its ATP-bound conformation, and p23 then interacts with the hsp90 to stabilize the complex. Stepwise assembly experiments have shown that hsp70 and hsp40 first interact with the receptor in an ATP-dependent reaction to produce a receptor·hsp70·hsp40 complex that is “primed” to be activated to the steroid-binding state in a second ATP-dependent step with hsp90, Hop, and p23. Successful use of the five-protein system with other substrates Indicates that it can assemble signal protein-hsp90 heterocomplexes whether the substrate is a receptor, a protein kinase, or a transcription factor. This purified system should facilitate understanding of how eukaryotlc hsp70 and hsp90 work together as essential components of a process that alters the conformations of substrate proteins to states that respond in signal transduction.
- Subjects :
- 0301 basic medicine
Conformational change
Macromolecular Substances
Receptors, Cell Surface
Plasma protein binding
Biology
Models, Biological
General Biochemistry, Genetics and Molecular Biology
Structure-Activity Relationship
03 medical and health sciences
0302 clinical medicine
polycyclic compounds
Animals
Drosophila Proteins
Humans
HSP70 Heat-Shock Proteins
HSP90 Heat-Shock Proteins
Immunophilins
Janus Kinases
Nucleotides
Protein-Tyrosine Kinases
Hsp90
Transport protein
Cell biology
Protein Transport
030104 developmental biology
CDC37
Multiprotein Complexes
030220 oncology & carcinogenesis
Chaperone (protein)
Hsp33
biology.protein
Signal transduction
Molecular Chaperones
Protein Binding
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 15353699 and 15353702
- Volume :
- 228
- Database :
- OpenAIRE
- Journal :
- Experimental Biology and Medicine
- Accession number :
- edsair.doi.dedup.....3dcc03a5f90e986ed1076aaf647c5723