SIS1

SIS1 is a gene in the budding yeast Saccharomyces cerevisiae that encodes Sis1, a member of the DnaJ/Hsp40 family of molecular co-chaperones. Sis1 functions as a J-domain protein that regulates the activity of Hsp70 chaperones, promoting substrate binding and the ATPase cycle necessary for protein folding and remodeling.

Sis1 belongs to the type I class of Hsp40s, typically containing an N-terminal J-domain, a glycine/phenylalanine-rich region, and a C-terminal domain that recognizes unfolded polypeptides. This structure enables Sis1 to interact with Hsp70 chaperones and client proteins, facilitating processes such as nascent-chain folding, quality control of misfolded proteins, and, in cooperation with other chaperones, protein disaggregation.

In yeast, Sis1 is found primarily in the cytosol but can localize to the nucleus under certain conditions. It operates within the cellular chaperone network, partnering with Hsp70 family members (such as Ssa proteins) and, in disaggregation contexts, with Hsp104 to refold or remodel proteins. Sis1 also participates in proteostasis during stress and contributes to the propagation and maintenance of several yeast prions, including [PSI+] and [URE3], by influencing the fragmentation and inheritance of prion aggregates.

Evolutionarily, SIS1 is conserved among fungi and has homologs in other eukaryotes within the DnaJ/Hsp40 family. In S. cerevisiae, it coexists with another Hsp40, Ydj1, which can have overlapping or distinct roles in chaperone function. Sis1 is widely used in studies of chaperone networks and prion biology, illustrating the function of co-chaperones in proteostasis.