Abstract
The heat shock 70 (Hsp70) family of molecular chaperones plays a central role in maintaining cellular proteostasis. Structurally, Hsp70s are composed of an N-terminal nucleotide binding domain (NBD) which exhibits ATPase activity, and a C-terminal substrate binding domain (SBD). The binding of ATP at the NBD and its subsequent hydrolysis influences the substrate binding affinity of the SBD through allostery. Similarly, peptide binding at the C-terminal SBD stimulates ATP hydrolysis by the N-terminal NBD. Interdomain communication between the NBD and SBD is facilitated by a conserved linker segment. Hsp70s form two main subgroups. Canonical Hsp70 members generally suppress protein aggregation and are also capable of refolding misfolded proteins. Hsp110 members are characterized by an extended lid segment and their function tends to be largely restricted to suppression of protein aggregation. In addition, the latter serve as nucleotide exchange factors (NEFs) of canonical Hsp70s. The linker of the Hsp110 family is less conserved compared to that of the canonical Hsp70 group. In addition, the linker plays a crucial role in defining the functional features of these two groups of Hsp70. Generally, the linker of Hsp70 is quite small and varies in size from seven to thirteen residues. Due to its small size, any sequence variation that Hsp70 exhibits in this motif has a major and unique influence on the function of the protein. Based on sequence data, we observed that canonical Hsp70s possess a linker that is distinct from similar segments present in Hsp110 proteins. In addition, Hsp110 linker motifs from various genera are distinct suggesting that their unique features regulate the flexibility with which the NBD and SBD of these proteins communicate via allostery. The Hsp70 linker modulates various structure-function features of Hsp70 such as its global conformation, affinity for peptide substrate and interaction with co-chaperones. The current review discusses how the unique features of the Hsp70 linker accounts for the functional specialization of this group of molecular chaperones.
Highlights
The heat shock 70 (Hsp70) family of molecular chaperones plays a central role in maintaining cellular proteostasis
Hsp110 linker motifs from various genera are distinct suggesting that their unique features regulate the flexibility with which the nucleotide binding domain (NBD) and substrate binding domain (SBD) of these proteins communicate via allostery
The structural conformation of Hsp70 is important for its functions such as ATP hydrolysis, substrate binding, stress response, structural integrity and oligomerization
Summary
The heat shock 70 (Hsp70)/E. coli Hsp (DnaK) family of molecular chaperones are among some of the most conserved proteins [1]. Hsp70s are ubiquitous molecules, not all of them are constitutively expressed (heat cognate proteins [Hsc]), but several of them are induced in response to cellular stress. Canonical Hsp represented by E. coli Hsp (DnaK) are capable of suppressing protein misfolding/aggregation as well as refold misfolded proteins [7,8,9]. Hsp70s’ high conservation level across species, functional characteristics of the model E. coli DnaK are generally mirrored by other canonical Hsp70s from other species. The co-operation of Hsp with co-chaperones propagates the functional valency of these otherwise conserved proteins
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