AI Article Synopsis
- Molecular chaperones help proteins fold and assemble, but how they target specific proteins is still unclear.
- Research using mouse genetics reveals that ZMYND10 is a new co-chaperone that helps the FKBP8-HSP90 complex specifically assist axonemal dynein proteins, which are vital for cilia movement.
- Without ZMYND10, there's disruption in dynein stability, leading to wider degradation of motor components, and specific mutations in ZMYND10 can further complicate this process, suggesting that related diseases like primary ciliary dyskinesia should be viewed as specific types of protein misfolding disorders.
Article Abstract
Molecular chaperones promote the folding and macromolecular assembly of a diverse set of 'client' proteins. How ubiquitous chaperone machineries direct their activities towards specific sets of substrates is unclear. Through the use of mouse genetics, imaging and quantitative proteomics we uncover that ZMYND10 is a novel co-chaperone that confers specificity for the FKBP8-HSP90 chaperone complex towards axonemal dynein clients required for cilia motility. Loss of ZMYND10 perturbs the chaperoning of axonemal dynein heavy chains, triggering broader degradation of dynein motor subunits. We show that pharmacological inhibition of FKBP8 phenocopies dynein motor instability associated with the loss of ZMYND10 in airway cells and that human disease-causing variants of ZMYND10 disrupt its ability to act as an FKBP8-HSP90 co-chaperone. Our study indicates that primary ciliary dyskinesia (PCD), caused by mutations in dynein assembly factors disrupting cytoplasmic pre-assembly of axonemal dynein motors, should be considered a cell-type specific protein-misfolding disease.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044906 | PMC |
| http://dx.doi.org/10.7554/eLife.34389 | DOI Listing |
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