To fold or to degrade? Proteins have to be folded to its native structure in order to perform its designated tasks and a failure to do so leads to deleterious effects. Chaperones as the name suggest prevents improper interactions and ensures proper functioning of the proteome.

Molecular chaperones are set of proteins that helps protein fold but without forming a final part of the structure (Kim et al., 2013). Heat shock protein 70 (Hsp70) is a chaperone involved in multiple function in the cell including protein folding, translocation, refolding, reactivation and degradation. In order for Hsp70 to perform its function it relies on multiple cofactors and nucleotide exchange factors (NEFs), and one such NEF is heat shock protein 110 (Hsp110), which is encoded by the HSPH1 gene. Hsp110's isoform Hsp105 alpha is cytoplasmic and Hsp105 beta is nucleoplasmic in localization (Saito et al, 2007). Hsp70 adopts two conformation open and closed. In the ADP-bound state Hsp70 exists in closed conformation with high affinity to the substrate proteins and upon interaction with NEFs (for example Hsp110) adopts an open conformation resulting in low substrate affinity. The repeated cycle of Hsp70 conformation results in proper folding or refolding of the proteins.

The ability of Hsp110 to bind or hold proteins (holding chaperone) in a folding competent state is still debated. Hsp110 protects luciferase from aggregating during thermal stress by binding directly to the denatured luciferase, thus assisting Hsp70 to fold or reactivate (Oh et al, 1997). Overexpression of Hsp110 reduced alpha-synuclein aggregation and spread of alpha-synuclein seeds resulting in reduced toxicity (Taguchi et al, 2019). Studies have also reported Hsp110 as a bona fide chaperone capable of reactivating misfolded proteins independent of Hsp70 (Mattoo et al, 2013, and Mattoo et al, 2014). Elevated nuclear Hsp110 levels in gastric cancer tissues have also been reported to be involved in cancer progression and poor prognosis (Kimura et al, 2016). Perhaps due to all these specialised and yet diverse roles it is not surprising to have a high concentration of Hsp110 in the cell.

References

Kim, Y.E., Hipp, M.S., Bracher, A., Hayer-Hartl, M. & Hartl, F.U. Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem 82, 323-55 (2013).

Saito Y, Yamagishi N. & Hatayama T. Different localization of Hsp105 family proteins in mammalian cells. Exp Cell Res. 313:3707?3717 (2007).

Oh, H.J., Chen, X. & Subjeck, J.R. Hsp110 protects heat-denatured proteins and confers cellular thermoresistance. J Biol Chem 272, 31636-40 (1997).

Mattoo, R.U., Sharma, S.K., Priya, S., Finka, A. & Goloubinoff, P. Hsp110 is a bona fide chaperone using ATP to unfold stable misfolded polypeptides and reciprocally collaborate with Hsp70 to solubilize protein aggregates. J Biol Chem 288, 21399-411 (2013).

Mattoo, R.U. & Goloubinoff, P. Molecular chaperones are nanomachines that catalytically unfold misfolded and alternatively folded proteins. Cell Mol Life Sci 71, 3311-25 (2014).

Kimura, A., Ogata, K., Altan, B., Yokobori, T., Ide, M., Mochiki, E., Toyomasu, Y., Kogure, N., Yanoma. T., Suzuki, M., Bai, T., Oyama, T & Kuwano, H. Nuclear heat shock protein 110 expression is associated with poor prognosis and chemotherapy resistance in gastric cancer. Oncotarget 7,18415-18423 (2016).

Taguchi, Y., Gorenberg, E.L., Nagy, M., Thrasher, D., Fenton, W.A., Volpicelli-Daley, L., Horwich, A.L & Chandra, S.S. Hsp110 mitigates ?-synuclein pathology in vivo. PNAS (2019).

Jayasankar Kaimal