Coordinated Activation of Hsp70 Chaperones

Abstract

Hsp70s are a ubiquitous family of molecular chaperones involved in many cellular processes. Two Hsp70s, Lhs1p and Kar2p, are required for protein biogenesis in the yeast endoplasmic reticulum. Here, we found that Lhs1p and Kar2p specifically interacted to couple, and coordinately regulate, their respective activities. Lhs1p stimulated Kar2p by providing a specific nucleotide exchange activity, whereas Kar2p reciprocally activated the Lhs1p adenosine triphosphatase (ATPase). The two ATPase activities are coupled, and their coordinated regulation is essential for normal function in vivo.

Hsp110 Cooperates with Different Cytosolic HSP70 Systems in a Pathway for de Novo Folding

“…For instance, in the endoplasmic reticulum, a distant Hsp110 homologue, Lhs1p, stimulates the ATPase activity of the endoplasmic reticulum Hsp70 Kar2p by acting as a nucleotide exchange factor, whereas Kar2p coordinately regulates Lhs1p activity by stimulating its ATPase (30). Interestingly, mammalian Hsp110 has been reported to inhibit the ATPase activity of nucleotide-loaded Hsp70 (29), which could be consistent with an Hsp110 nucleotide exchange activity.…”

“…In S. cerevisiae, cells lacking Sse1p are slow growing and temperature-sensitive (13), and genetic studies also implicate Sse1p in Hsp90-dependent processes (24,28). Interestingly, biochemical studies suggest that Hsp110 chaperones may be involved in the regulation of Hsp70 ATP hydrolysis and that Hsp70 may have some stimulatory activity on Hsp110 ATPase as well (29,30).…”

Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco–Sjögren syndrome

“…HSPA5 encoding GRP78 and HYOU1 were selected because of known interaction or overlapping function with SIL1. 16,23 Although both HSPA5 and HYOU1 mouse knockout models show embryonic lethality, 24 mutations leading to for example reduced protein expression or altered protein function could result in MSS phenotype. The AARS gene was considered a candidate on the basis of similar cerebellar phenotype in mouse models.…”

Secretory Protein Biogenesis and Traffic in the Early Secretory Pathway

“…The Hsp70 remains bound to unfolded substrates until ADP is released with this Hsp70 ATPase cycle governed by specific DnaJ-like proteins that stimulate ATP hydrolysis and nucleotide exchange factors that drive ADP release (Hartl 1996;Bukau and Horwich 1998). In yeast, the Hsp70 Kar2 plays a prominent role in ER folding in concert with the related Hsp70 protein Lhs1 (Rose et al 1989;Baxter et al 1996;Brodsky et al 1999;Steel et al 2004). For Kar2, the known DnaJ-like stimulating factors include Sec63, Scj1, and Jem1 (Schlenstedt et al 1995;Nishikawa and Endo 1997), whereas the GrpE family member Sil1 and, surprisingly, the unrelated ATPase Lhs1 serve as nucleotide exchange factors (Hale et al 2010).…”