Hsp70 Molecular Chaperones: Emerging Roles in Human Disease and Identification of Small Molecule Modulators

Brodsky, Jeffrey L.; Chiosis, Gabriela

doi:10.2174/156802606777811997

Cited by 188 publications

(201 citation statements)

References 142 publications

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“…It is not surprising that chaperone sequences and triose phosphate dehydrogenases (in the metabolic enzyme class) are strongly conserved, because these are genes whose sequences are highly conserved across the biome (3,21,60). Their primary locations are intracellular.…”

Section: Prevalence Of Cell Wall-related Sequences In Fungimentioning

confidence: 99%

“…The commonalities identified here suggest that each eukaryotic lineage has conserved the mechanism to generate diverse extracellular structures but has altered the products of the mechanism in their ancestor to form cell walls (in plants) or some other extracellular matrices (in metazoans). This conserved mechanism uses GPI synthesis and processing enzymes, carbohydrate-processing enzymes, and chaperones to enable the localization and proper folding of the proteins (3,21,40,41).…”

Section: Prevalence Of Cell Wall-related Sequences In Fungimentioning

confidence: 99%

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Conserved Processes and Lineage-Specific Proteins in Fungal Cell Wall Evolution

et al. 2007

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The cell wall is a defining organelle that differentiates fungi from its sister clades in the opisthokont superkingdom. With a sensitive technique to align low-complexity protein sequences, we have identified 187 cell wall-related proteins in Saccharomyces cerevisiae and determined the presence or absence of homologs in 17 other fungal genomes. There were both conserved and lineage-specific cell wall proteins, and the degree of conservation was strongly correlated with protein function. Some functional classes were poorly conserved and lineage specific: adhesins, structural wall glycoprotein components, and unannotated open reading frames. These proteins are primarily those that are constituents of the walls themselves. On the other hand, glycosyl hydrolases and transferases, proteases, lipases, proteins in the glycosyl phosphatidyl-inositol-protein synthesis pathway, and chaperones were strongly conserved. Many of these proteins are also conserved in other eukaryotes and are associated with wall synthesis in plants. This gene conservation, along with known similarities in wall architecture, implies that the basic architecture of fungal walls is ancestral to the divergence of the ascomycetes and basidiomycetes. The contrasting lineage specificity of wall resident proteins implies diversification. Therefore, fungal cell walls consist of rapidly diversifying proteins that are assembled by the products of an ancestral and conserved set of genes.

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Section: Prevalence Of Cell Wall-related Sequences In Fungimentioning

confidence: 99%

Section: Prevalence Of Cell Wall-related Sequences In Fungimentioning

confidence: 99%

Conserved Processes and Lineage-Specific Proteins in Fungal Cell Wall Evolution

et al. 2007

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“…They play essential roles in every aspect of cellular protein homeostasis including protein folding, transportation across membrane, assembly, degradation, and quality control. Due to the fundamental importance of maintaining protein homeostasis, Hsp70s are connected with many human diseases including various cancers and neurodegenerative diseases (Muchowski and Wacker 2005;Brodsky and Chiosis 2006;Balch et al 2008;Evans et al 2010;Murphy 2013). Qingdai Liu, Hongtao Li, Ying Yang, and Xueli Tian contributed equally to this work Hsp70s are highly conserved.…”

Section: Introductionmentioning

confidence: 99%

A disulfide-bonded DnaK dimer is maintained in an ATP-bound state

Liu

Yang

et al. 2017

Cell Stress and Chaperones

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DnaK, a major Hsp70 molecular chaperones in Escherichia coli, is a widely used model for studying Hsp70s. We recently solved a crystal structure of DnaK in complex with ATP and showed that DnaK was packed as a dimer in the crystal structure. Our previous biochemical studies supported the formation of a specific DnaK dimer as observed in the crystal structure in solution in the presence of ATP and suggested an important role of this dimer in efficient interaction with Hsp40 co-chaperones. In this study, we dissected the biochemical properties of this DnaK dimer. To restrict DnaK in this dimer form, we mutated two residues on the dimer interface to cysteine, A303C, and H541C. Upon oxidation, this DnaK-A303C-H541C protein formed a specific dimer linked by disulfide bonds formed between A303C and H541C only in the presence of ATP, consistent with the crystal structure. Intriguingly, this disulfide-bond-linked dimer of DnaK-A303C-H541C has reduced ATPase activity and decreased affinity for peptide substrate. More interestingly, unlike wild-type DnaK, the peptide substrate-binding kinetics of this dimer is drastically accelerated even in the absence of ATP, suggesting this dimer is restricted in an ATP-bound conformation regardless of nucleotide bound, which was further supported by our analysis using tryptophan fluorescence and ATP-induced peptide release. Thus, formation of the dimer restricted DnaK in an ATP-bound state and blocked the progression through the chaperone cycle. Productive progression through the chaperone cycle requires the dissociation of this transient dimer. Surprisingly, a significantly compromised interaction with Hsp40 co-chaperone was observed for this disulfide-bond-linked dimer. Thus, dissociation of this DnaK dimer is equally crucial for efficient Hsp40 interaction. An initial interaction between Hsp70 and Hsp40 requires the formation of DnaK dimer; but a stable Hsp70-Hsp40 interaction may follow the dissociation of the dimer.

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“…Hsp70 is abundantly expressed in many human tumors and this often correlates with metastasis and poor outcome in cancer patients (Brodsky and Chiosis, 2006;Patury et al, 2009). Up-regulated Hsp70 function is critical for the growth and survival of different human tumor cell lines (Brodsky and Chiosis, 2006;Patury et al, 2009;Powers et al, 2008). In light of the ample structural data available on this molecular chaperone, Hsp70 appears as an attractive putative drug target for the treatment of cancer.…”

Section: Cellular Functions Of Hsp70mentioning

confidence: 99%

Structure and function of Hip, an attenuator of the Hsp70 chaperone cycle

Hartl

Bracher

2013

Nat Struct Mol Biol

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The Hsp70-interacting protein, Hip, cooperates with the chaperone Hsp70 in protein folding and prevention of aggregation. Hsp70 interacts with non-native protein substrates in an ATP-dependent reaction cycle regulated by J-domain proteins and nucleotide exchange factors (NEFs). Hip is thought to delay substrate release by slowing ADP dissociation from Hsp70. Here we present crystal structures of the dimerization domain and the tetratricopeptide repeat (TPR) domain of rat Hip. As shown in a cocrystal structure, the TPR core of Hip interacts with the Hsp70 ATPase domain through an extensive interface, to form a bracket that locks ADP in the binding cleft. Hip and NEF binding to Hsp70 are mutually exclusive, and thus Hip attenuates active cycling of Hsp70-substrate complexes. This mechanism explains how Hip enhances aggregation prevention by Hsp70 and facilitates transfer of specific proteins to downstream chaperones or the proteasome

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Hsp70 Molecular Chaperones: Emerging Roles in Human Disease and Identification of Small Molecule Modulators

Cited by 188 publications

References 142 publications

Conserved Processes and Lineage-Specific Proteins in Fungal Cell Wall Evolution

Conserved Processes and Lineage-Specific Proteins in Fungal Cell Wall Evolution

A disulfide-bonded DnaK dimer is maintained in an ATP-bound state

Structure and function of Hip, an attenuator of the Hsp70 chaperone cycle

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