Processing of chaperone clients in C. elegans
Final Report Abstract
During the funding period of these projects, we gained insight into the function of the chaperone systems Hsp90 and Hsc70. We started understanding, why they interact with their clients and which events modulate this interaction, be it nucleotide-binding to the kinase or ligand-binding to the steroid receptor. Further we learned how these complexes with the many cofactors are arranged and how we can investigate their complexity. These are important insights for protein complexes identified about 30 years ago. Beyond this we learned which diseases or nematode model diseases can originate from malfunction of the chaperone system and disturbed proteostasis. These include debilitating defects caused by missing chaperone proteins, like HSC-70, HSP-90, UNC-45 and UNC-23 in nematodes. A third level are modulating effects that can be observed, when single-point mutations in HSC-70, HSP-90, PPH-5, CDC-37 or full depletion of DNJ-13 can be induced and used to repair misbalanced systems or even restore functionality. Apparently the proteostasis system can be modulated in order to cause diseases and in order to prevent or heal diseases and the right level of chaperone and cochaperone functions appears to be the path in the middle that leads to a healthy life in nematodes. As most of the investigated proteins are found with high levels of homology also in mammalian systems, it will be of interest to understand, whether the same cellular functions are supported also in the human organism. During the project there were a few surprises, e,g, our inability to purify sufficient amounts of MBK-2, which together with the partially absent interaction with HSP-90 of the other kinases did not allow to establish a second kinase model system. Also, our difficulty in obtaining sufficient nematode lines for comparison of in vivo effects was surprising, but possibly also due to the difficulty in transferring the knowledge about plasmid injections into nematodes within the fairly small research group. Beyond that we had hoped for a faster development of the electron microscopic evaluation of the cross-linked protein complexes, but this project was designed with a timeline that possibly would have required a follow-up grant to the current study. Despite these shortcomings, the grant had included several projects in different development states and therefore a compensation of these work packages with other more extensive and successful work packages could be performed.
Publications
- Hsp90-downregulation influences the heat-shock response, innate immune response and onset of oocyte development in nematodes. PLoS One. 2017 Oct 27;12(10):e0186386
Eckl J, Sima S, Marcus K, Lindemann C, Richter K
(See online at https://doi.org/10.1371/journal.pone.0186386) - Regulation of the Hsp90 system. Biochim Biophys Acta Mol Cell Res. 2018 Jun;1865(6):889-897
Sima S, Richter K.
(See online at https://doi.org/10.1016/j.bbamcr.2018.03.008) - Head-bent resistant Hsc70 variants show reduced Hsp40 affinity and altered protein folding activity. Sci Rep. 2019 Aug 16;9(1):11955
Papsdorf K, Sima S, Schmauder L, Peter S, Renner L, Hoffelner P, Richter K.
(See online at https://doi.org/10.1038/s41598-019-48109-0) - Glucocorticoid receptor complexes form cooperatively with the Hsp90 co-chaperones Pp5 and FKBPs. Sci Rep. 2020 Jul 1;10(1):10733
Kaziales A, Barkovits K, Marcus K, Richter K
(See online at https://doi.org/10.1038/s41598-020-67645-8) - Glucocorticoid resistance conferring mutation in the C-terminus of GR alters the receptor conformational dynamics. Sci Rep. 2021 Jun 15;11(1):12515
Kaziales A, Rührnößl F, Richter K.
(See online at https://doi.org/10.1038/s41598-021-92039-9) - hsp-90 and unc-45 depletion induce characteristic transcriptional signatures in coexpression cliques of C. elegans. Sci Rep. 2021 Jun 18;11(1):12852
Schmauder L, Richter K.
(See online at https://doi.org/10.1038/s41598-021-91690-6) - HSP-90/kinase complexes are stabilized by the large PPIase FKB-6. Sci Rep. 2021 Jun 11;11(1):12347
Sima S, Barkovits K, Marcus K, Schmauder L, Hacker SM, Hellwig N, Morgner N, Richter K
(See online at https://doi.org/10.1038/s41598-021-91667-5) - Nematode CDC-37 and DNJ-13 form complexes and can interact with HSP-90., Sci Rep. 2021 Nov 1;11(1):21346
Schmauder L, Absmeier E, Bepperling A, Barkovits K, Marcus K, Richter K.
(See online at https://doi.org/10.1038/s41598-021-00885-4) - Binding of the HSF-1 DNA-binding domain to multimeric C. elegans consensus HSEs is guided by cooperative interactions., Sci Rep. 2022 May 28;12(1):8984
Schmauder L, Sima S, Hadj AB, Cesar R, Richter K
(See online at https://doi.org/10.1038/s41598-022-12736-x)
