Mayer MP, Bukau BHsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 62:670-684

Zentrum für Molekulare Biologie (ZMBH), Universität Heidelberg, Im Neuenheimer Feld 282, 69120, Heidelberg, Germany.
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.81). 04/2005; 62(6):670-84. DOI: 10.1007/s00018-004-4464-6
Source: PubMed

ABSTRACT Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a large variety of protein folding processes in the cell by transient association of their substrate binding domain with short hydrophobic peptide segments within their substrate proteins. The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus, ATP binding and hydrolysis are essential in vitro and in vivo for the chaperone activity of Hsp70 proteins. This ATPase cycle is controlled by co-chaperones of the family of J-domain proteins, which target Hsp70s to their substrates, and by nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this chaperone cycle. For specific tasks the Hsp70 cycle is coupled to the action of other chaperones, such as Hsp90 and Hsp100.

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    • "HSPs have been extensively utilized as biosensors to monitor environmental stress. They are very sensitive to, and altered even at sub-lethal doses of contaminants (Mayer and Bukau, 2005). HSPs function as intra-cellular chaperones that play important roles in protein folding (Mayer and Bukau, 2005; Mayer, 2013). "
    • "For these reasons, significant consideration has been given to the functional role of HSPA2 both in sperm development (Huszar et al., 1997, 2000, 2006; Tian et al., 2014; reviewed by Scieglinska and Krawczyk, 2015) and in sperm –zona pellucida interaction (Redgrove et al., 2013). HSPA2 is a testis-enriched member of the HSP70 family of chaperones, which is primarily responsible for preventing the aggregation of misfolded proteins (Mayer and Bukau, 2005) and for fulfilling secondary roles in the transmembrane transport of client proteins (Huszar et al., 2000; Dun et al., 2012) and the formation of multimeric protein complexes (Redgrove et al., 2011). The importance of HSPA2 for sperm development has been highlighted by targeted ablation of the gene, which results in a phenotype of complete male infertility (Dix et al., 1997). "
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    ABSTRACT: While a large cohort of sperm surface receptors underpin sperm-oocyte adhesion processes, our recent work has revealed that the molecular chaperone Heat Shock Protein A2 (HSPA2) is a key regulator of zona pellucida-receptor complex assembly in our own species. Indeed, in the infertile population, spermatozoa that fail to interact with the zona pellucida of the oocyte consistently lack HSPA2 protein expression. While the mechanisms behind this protein deficiency are under consideration, BCL2-associated athanogene 6 (BAG6) has been identified as a key regulator of HSPA2 stability in mouse germ cells. However, in the human, the presence of BAG family proteins remains completely uncharacterized. Consequently, this study aimed to determine the presence of BAG6 in human sperm cells and to characterize its putative interaction with HSPA2 throughout sperm cell development. BAG6 was shown to co-localize with HSPA2 in human testicular germ cells and epididymal spermatozoa. Similarly, BAG6 was identified in the equatorial region of non-capacitated spermatozoa but underwent a marked relocation to the anterior region of the head upon the induction of capacitation in these cells. Protein-protein interaction assays revealed the stable interaction of BAG6 and HSPA2 proteins in mature spermatozoa. Furthermore, examination of the spermatozoa of infertile men with zona pellucida binding defects, related to a lack of HSPA2, revealed a concomitant deficiency in BAG6 protein expression. In view of the findings described in this study, we propose that BAG6 is likely a key regulator of HSPA2 stability/function in human germ cells. Moreover, its under-representation in spermatozoa with zona pellucida binding deficiency suggests that BAG6 may be an important candidate to study for a further understanding of male idiopathic infertility.
    Molecular Human Reproduction 07/2015; DOI:10.1093/molehr/gav041 · 3.75 Impact Factor
    • "The peptidebinding domain is further subdivided into a β-sandwich subdomain (18 kDa), which is the substrate-binding domain and an α-helical subdomain (Flaherty et al. 1990; Zhu et al. 1996; Wang et al. 1993). Hsp70s perform their roles due to their ability to interact with hydrophobic peptide segments of proteins in an ATP-dependent manner (Mayer and Bukau 2005). Depending on the ATP cycle, Hsp70 binds to the substrate peptide of unfolded or denatured proteins at its either normal or stress state (Szabo et al. 1994; Bukau and Horwich 1998). "
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    ABSTRACT: This study describes the first detailed molecular characterization of the heat shock protein 70 (Hsp70) gene from Sorghum bicolor, MN1618 designated as SbHsp70-1. The full-length cDNA of SbHsp70-1 consists of 2524 bp with a 1950 bp open reading frame, which encodes a protein of 649 amino acids. SbHsp70-1 is a cytoplasmic protein with high homology to other plant Hsp70s, especially grain crops. Recombinant SbHsp70-1 was able to bind and hydrolyse ATP in a dose-dependent manner, suggesting that SbHsp70-1 functions as an ATPase. Immunoblot assays showed that the expression of SbHsp70-1 is induced at temperatures of 37, 45, and 4 °C but reduced at 42 °C. In addition, the SbHsp70-1 mRNA transcript is constitutively expressed in both leaves and stem but is significantly increased upon heat shock at 42 °C. Upon cold shock at 4 °C, SbHsp70-1 mRNA transcript level increased in the leaf, but no significant change was observed in the stem. In addition, expression of the pET28a-SbHsp70-1 construct in Escherichia coli cells under heat stress resulted in their survival even at higher temperature (65 °C). Our results suggest that SbHsp70-1 is a heat-inducible protein that confer thermal tolerance to bacterial cells and can be claimed as a promising target to study stress tolerance in crops.
    Cell Stress and Chaperones 06/2015; 20(5). DOI:10.1007/s12192-015-0591-2 · 3.16 Impact Factor
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