Selective Binding of HSC70 and its Co-Chaperones to Structural Hotspots on CFTR.

Scientific Reports
Imad BaakliniJason C Young

Abstract

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel cause cystic fibrosis. Chaperones, including HSC70, DNAJA1 and DNAJA2, play key roles in both the folding and degradation of wild-type and mutant CFTR at multiple cellular locations. DNAJA1 and HSC70 promote the folding of newly synthesized CFTR at the endoplasmic reticulum (ER), but are required for the rapid turnover of misfolded channel at the plasma membrane (PM). DNAJA2 and HSC70 are also involved in the ER-associated degradation (ERAD) of misfolded CFTR, while they assist the refolding of destabilized channel at the PM. These outcomes may depend on the binding of chaperones to specific sites within CFTR, which would be exposed in non-native states. A CFTR peptide library was used to identify binding sites for HSC70, DNAJA1 and DNAJA2, validated by competition and functional assays. Each chaperone had a distinct binding pattern, and sites were distributed between the surfaces of the CFTR cytosolic domains, and domain interfaces known to be important for channel assembly. The accessibility of sites to chaperones will depend on the degree of CFTR folding or unfolding. Different folded states may be recognized by unique combinations of HSC70, ...Continue Reading

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Citations

Mar 21, 2021·Medical Oncology·Ameneh JafariMostafa Rezaei-Tavirani
Jul 6, 2020·Analytical Biochemistry·Samuel K Estabrooks, Jeffrey L Brodsky
Sep 11, 2021·Nature Communications·Zhiqiang HouLukasz A Joachimiak
Sep 28, 2021·Biochimica Et Biophysica Acta. Proteins and Proteomics·Noeli Soares Melo SilvaJúlio César Borges

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