Sequential mechanism of solubilization and refolding of stable protein aggregates by a bichaperone network

Pierre Goloubinoff, Axel Mogk, Anat Peres Ben Zvi, Toshifumi Tomoyasu, Bernd Bukau

Research output: Contribution to journalArticlepeer-review

494 Scopus citations

Abstract

A major activity of molecular chaperones is to prevent aggregation and refold misfolded proteins. However, when allowed to form, protein aggregates are refolded poorly by most chaperones. We show here that the sequential action of two Escherichia coli chaperone systems, CIpB and DnaK-DnaJ-GrpE, can efficiently solubilize excess amounts of protein aggregates and refold them into active proteins. Measurements of aggregate turbidity, Congo red, and 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid binding, and of the disaggregation/refolding kinetics by using a specific CIpB inhibitor, suggest a mechanism where (i) CIpB directly binds protein aggregates, ATP induces structural changes in CIpB, which (ii) increase hydrophobic exposure of the aggregates and (iii) allow DnaK-DnaJ-GrpE to bind and mediate dissociation and refolding of solubilized polypeptides into native proteins. This efficient mechanism, whereby chaperones can catalytically solubilize and refold a wide variety of large and stable protein aggregates, is a major addition to the molecular arsenal of the cell to cope with protein damage induced by stress or pathological states.

Original languageEnglish
Pages (from-to)13732-13737
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number24
DOIs
StatePublished - 23 Nov 1999
Externally publishedYes

Keywords

  • CIpB
  • Congo red
  • DnaK
  • Hsp104
  • Protein disaggregation

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