Biomedical subjects

Csaba Söti

Publications and source records attributed to Csaba Söti.

5 recordsLinked to original sources

PubMed2007

Chaperones as parts of cellular networks.

The most important interactions between cellular molecules have a high affinity, are unique and specific, and require a network approach for a detailed description. Molecular chaperones usually have many first and second neighbors in protein-protein interaction networks and they play a prominent role in signaling and transcriptional regulatory networks of the cell. Chaperones may uncouple protein, signaling, membranous, organellar and transcriptional networks during stress, which gives an additional protection for the cell at the network-level. Recent advances uncovered that chaperones act as genetic buffers stabilizing the phenotype of various cells and organisms. This chaperone effect on the emergent properties of cellular networks may be generalized to proteins having a specific, central position and low affinity, weak links in protein networks. Cellular networks are preferentially remodeled in various diseases and aging, which may help us to design novel therapeutic and anti-aging strategies.

Animals↗

PubMed2003

Molecular chaperones, stress proteins and redox homeostasis.

Protection against oxidative stress is highly interrelated with the function of the most ancient cellular defense system, the network of molecular chaperones, heat shock, or stress-proteins. These ubiquitous, conserved proteins help other proteins and macromolecules to fold or re-fold and reach their final, native conformation. Redox regulation of protein folding becomes especially important during the preparation of extracellular proteins to the outside oxidative milieu, which should take place in a gradual and step-by-step controlled manner in the endoplasmic reticulum or in the periplasm. Several chaperones, such as members of the Hsp33 family in yeast and the plethora of small heat shock proteins as well as one of the major chaperones, Hsp70 are able to act against cytoplasmic oxidative damage. Abrupt changes of cellular redox status lead to chaperone induction. The function of several chaperones is tightly regulated by the surrounding redox conditions. Moreover, our recent data suggest that chaperones may act as a central switchboard for the transmission of redox changes in the life of the cell.

Aging↗

PubMed2002

Chaperones and aging: role in neurodegeneration and in other civilizational diseases.

Chaperones are highly conserved proteins responsible for the preservation and repair of the correct conformation of cellular macromolecules, such as proteins, RNAs, etc. Environmental stress leads to chaperone (heat-shock protein, stress protein) induction reflecting the protective role of chaperones as a key factor for cell survival and in repairing cellular damage after stress. The present review summarizes our current knowledge about the chaperone-deficiency in the aging process, as well as the possible involvement of chaperones in neurodegenerative diseases, such as in Alzheimer's, Parkinson's, Huntington- and prion-related diseases. We also summarize a recent theory implying chaperones as "buffers" of variations in the human genome, which role probably increased during the last 200 years of successful medical practice minimizing natural selection. Chaperone-buffered, silent mutations may be activated during the aging process, which leads to the phenotypic exposure of previously hidden features and might contribute to the onset of polygenic diseases, such as atherosclerosis, cancer, diabetes and several neurodegenerative diseases.

Aging↗

PubMed2001

A Nucleotide-dependent molecular switch controls ATP binding at the C-terminal domain of Hsp90. N-terminal nucleotide binding unmasks a C-terminal binding pocket.

In vivo function of the molecular chaperone Hsp90 is ATP-dependent and requires the full-length protein. Our earlier studies predicted a second C-terminal ATP-binding site in Hsp90. By applying direct biochemical approaches, we mapped two ATP-binding sites and unveiled the C-terminal ATP-binding site as the first example of a cryptic chaperone nucleotide-binding site, which is opened by occupancy of the N-terminal site. We identified an N-terminal gamma-phosphate-binding motif in the middle domain of Hsp90 similar to other GHKL family members. This motif is adjacent to the phosphate-binding region of the C-terminal ATP-binding site. Whereas novobiocin disrupts both C- and N-terminal nucleotide binding, we found a selective C-terminal nucleotide competitor, cisplatin, that strengthens the Hsp90-Hsp70 complex leaving the Hsp90-p23 complex intact. Cisplatin may provide a pharmacological tool to dissect C- and N-terminal nucleotide binding of Hsp90. A model is proposed on the interactions of the two nucleotide-binding domains and the charged region of Hsp90.

Adenosine Triphosphate↗

PubMedDate not supplied

Chaperone function and chaperone overload in the aged. A preliminary analysis.

Chaperones have an important role in the repair of proteotoxic damage, which is greatly increased in aged subjects. Chaperone levels and expression were subject of numerous studies in aged organisms. However, there were only very few attempts to measure chaperone activity in aged animals. Here, we report our initial studies showing a decreased chaperone capacity of liver cytosol from aged rats compared to those of young counterparts. The amount of Hsc70/Hsp70 was not significantly different in livers of young and aged rats. On the contrary, old animals showed a significant decrease in their hepatic Hsp90 content, which may explain their decreased chaperone activity. The observed decrease in chaperone capacity may also reflect a direct proteotoxic damage of chaperones, or an increase in chaperone occupancy, i.e. a 'chaperone overload' due to the increased amount of damaged hepatic proteins in aged rats. Experiments are in progress to elucidate the mechanism of the observed age-induced changes in chaperone function.

Aging↗