For example, the Hsp70 substrate binding domain (PDBID: 1DKX) and the Hsp70 ATPase domain (PDBID: 1DKG) may be docked into hypothetical combined structures. Developments in this field have bypassed the need to combine structural information for component functional domains to predict their interactions. Unlike crystal structures of the other chaperones, the structures of the large hexameric Hsp104 were commonly determined through cryoelectron microscopy.
Hsp104s, on the other hand, currently have only 18 entries. Hsp90s, which have been associated with the refinement of receptor protein structures, currently have 541 entries. This disparity in distribution coincides with several factors: (1) Clinical significance, (2) structure complexity, and (3) ease of generation. In contrast, most entries deposited for Hsp70 and Hsp90 were from Homo sapiens, and the limited number of structures available for Hsp104 were mainly from Saccharomyces cerevisiae. The majority of the structures for Hsp60 are from E. The sampling of structures from different organisms is also not uniform. The most structures are available for Hsp90 with 541 entries, while several Hsp families and their homologs had more limited entries available (e.g., small Hsps (14 entries) Hsp104 (18 entries) Hsp104 homolog, ClpA (13 structures)). Hsp90s form multidomain V-shaped structures whose scissor-like motion helps refine receptor proteins, and the Hsp104s form hexameric rings that facilitate unfolding by a ratchet-like mechanism.Ī survey of the molecular structures deposited at the Protein Data Bank (PDB) ( ) as of August 2019 shows an uneven distribution across the five classes. Hsp70s and the small Hsps, on the other hand, adopt modular “clamps” for protecting extended hydrophobic structures in their targets. The Hsp60s adopt a barrel-like Anfinsen cage structure for sequestered folding of target proteins. Aside from their differences in size, the structures of these different classes are quite divergent. Further experimentation revealed several types of functions for different chaperone proteins, which may be attributed to the diversity of their structures.Ĭurrent structural information divides the chaperones into five major classes based on their observed molecular weights: Hsp60, Hsp70, Hsp90, Hsp104, and the small Hsps. The functions of these proteins were validated with the generation of recombinant versions of the proteins that performed their expected functions outside the original cellular environment. Expression of these proteins was increased with heat shock treatment, leading to their label as heat shock proteins (Hsps). These genes are bacterial homologs of Hsp60, Hsp10, Hsp70, Hsp40, and the nucleotide exchange factor for the Hsp70/Hsp40 machine. The disruption of groEL, groES, dnaK, dnaJ, and grpE was found to have deleterious effects for the growth of the bacteriophage. The first of these chaperone proteins was found by Sternberg in 1973 in studies of mutations that disrupted bacteriophage λ head formation. Ĭonsidering the dense population of the cytosol (average protein conc: 150 mg/mL), Finka and Goloubinoff proposed an inherent need to protect nascent polypeptides from “unwanted associations” that prevent the attainment of the functional protein fold. While this simple and elegant principle governs most biological systems, literature from both the distant and recent past have cited complications in the cellular environment that may disrupt the flow of genetic information.
The central dogma of molecular biology states that genes are transcribed into messenger RNAs, which are then translated into the proteins that carry out cellular functions.
The structures of domains and the associated functions are discussed in order to illustrate the rationale for the proposed unfoldase function. When possible, it discusses the complete structures for these proteins, and the types of molecular machines to which they have been assigned. It reviews the currently available molecular structures in the Protein Data Bank for several classes of Hsps (Hsp60, Hsp70, Hsp90, and Hsp104). This current article focuses on the resolved structural bases for these functions. Onto this is added specializations that allow the different family members to perform various cellular functions.
The term “unfoldases” has been proposed, as this basic function is shared by most members of this protein family. However, neither label encompasses the breadth of these proteins’ functional capabilities. These chaperone proteins also increased in expression as a response to heat shock, hence their label as heat shock proteins (Hsps). These proteins’ ability to prevent unwanted associations led to their being called chaperones. Thirty years ago a class of proteins was found to prevent the aggregation of Rubisco.
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