scholarly journals HSP-90/kinase complexes are stabilized by the large PPIase FKB-6

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Siyuan Sima ◽  
Katalin Barkovits ◽  
Katrin Marcus ◽  
Lukas Schmauder ◽  
Stephan M. Hacker ◽  
...  

AbstractProtein kinases are important regulators in cellular signal transduction. As one major type of Hsp90 client, protein kinases rely on the ATP-dependent molecular chaperone Hsp90, which maintains their structure and supports their activation. Depending on client type, Hsp90 interacts with different cofactors. Here we report that besides the kinase-specific cofactor Cdc37 large PPIases of the Fkbp-type strongly bind to kinase•Hsp90•Cdc37 complexes. We evaluate the nucleotide regulation of these assemblies and identify prominent interaction sites in this quaternary complex. The synergistic interaction between the participating proteins and the conserved nature of the interaction suggests functions of the large PPIases Fkbp51/Fkbp52 and their nematode homolog FKB-6 as contributing factors to the kinase cycle of the Hsp90 machinery.

2015 ◽  
Author(s):  
◽  
Jason Neville Sterrenberg

The therapeutic potential of stem cells is already being harnessed in clinical trails. Of even greater therapeutic potential has been the discovery of mechanisms to reprogram differentiated cells into a pluripotent stem cell-like state known as induced pluripotent stem cells (iPSCs). Stem cell nature is governed and maintained by a hierarchy of transcription factors, the apex of which is OCT4. Although much research has elucidated the transcriptional regulation of OCT4, OCT4 regulated gene expression profiles and OCT4 transcriptional activation mechanisms in both stem cell biology and cellular reprogramming to iPSCs, the fundamental biochemistry surrounding the OCT4 transcription factor remains largely unknown. In order to analyze the biochemical relationship between HSP90 and human OCT4 we developed an exogenous active human OCT4 expression model with human OCT4 under transcriptional control of a constitutive promoter. We identified the direct interaction between HSP90 and human OCT4 despite the fact that the proteins predominantly display differential subcellular localizations. We show that HSP90 inhibition resulted in degradation of human OCT4 via the ubiquitin proteasome degradation pathway. As human OCT4 and HSP90 did not interact in the nucleus, we suggest that HSP90 functions in the cytoplasmic stabilization of human OCT4. Our analysis suggests HSP90 inhibition inhibits the transcriptional activity of human OCT4 dimers without affecting monomeric OCT4 activity. Additionally our data suggests that the HSP90 and human OCT4 complex is modulated by phosphorylation events either promoting or abrogating the interaction between HSP90 and human OCT4. Our data suggest that human OCT4 displays the characteristics describing HSP90 client proteins, therefore we identify human OCT4 as a putative HSP90 client protein. The regulation of the transcription factor OCT4 by HSP90 provides fundamental insights into the complex biochemistry of stem cell biology. This may also be suggestive that HSP90 not only regulates stem cell biology by maintaining routine cellular homeostasis but additionally through the direct regulation of pluripotency factors.


2015 ◽  
Vol 290 (52) ◽  
pp. 30843-30854 ◽  
Author(s):  
Julia M. Eckl ◽  
Matthias J. Scherr ◽  
Lee Freiburger ◽  
Marina A. Daake ◽  
Michael Sattler ◽  
...  

2012 ◽  
Vol 446 (2) ◽  
pp. e5-e7 ◽  
Author(s):  
Brian E. Ellis

Plants contain hundreds of protein kinases that are believed to provide cellular signal transduction services, but the identities of the proteins they are targeting are largely unknown. Using an Arabidopsis MAPK (mitogen-activated protein kinase) (MPK6) as a model, Sörensson et al. describe in this issue of the Biochemical Journal how arrayed combinatorial peptide scanning offers an efficient route to discovery of new potential kinase substrates.


2011 ◽  
Vol 287 (2) ◽  
pp. 1406-1414 ◽  
Author(s):  
Barbara Baldo ◽  
Andreas Weiss ◽  
Christian N. Parker ◽  
Miriam Bibel ◽  
Paolo Paganetti ◽  
...  

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 999
Author(s):  
Olga K. Parfenova ◽  
Vladimir G. Kukes ◽  
Dmitry V. Grishin

Main forms of cellular signal transmission are known to be autocrine and paracrine signaling. Several cells secrete messengers called autocrine or paracrine agents that can bind the corresponding receptors on the surface of the cells themselves or their microenvironment. Follistatin and follistatin-like proteins can be called one of the most important bifunctional messengers capable of displaying both autocrine and paracrine activity. Whilst they are not as diverse as protein hormones or protein kinases, there are only five types of proteins. However, unlike protein kinases, there are no minor proteins among them; each follistatin-like protein performs an important physiological function. These proteins are involved in a variety of signaling pathways and biological processes, having the ability to bind to receptors such as DIP2A, TLR4, BMP and some others. The activation or experimentally induced knockout of the protein-coding genes often leads to fatal consequences for individual cells and the whole body as follistatin-like proteins indirectly regulate the cell cycle, tissue differentiation, metabolic pathways, and participate in the transmission chains of the pro-inflammatory intracellular signal. Abnormal course of these processes can cause the development of oncology or apoptosis, programmed cell death. There is still no comprehensive understanding of the spectrum of mechanisms of action of follistatin-like proteins, so the systematization and study of their cellular functions and regulation is an important direction of modern molecular and cell biology. Therefore, this review focuses on follistatin-related proteins that affect multiple targets and have direct or indirect effects on cellular signaling pathways, as well as to characterize the directions of their practical application in the field of biomedicine.


2021 ◽  
Vol 11 (3) ◽  
pp. 3871-3886

Inhibition of Hsp90 disrupts the Hsp90 client protein complex, resulting in its breakdown. Phytochemicals from reported anticancer plants were screened against the orthosteric site of Hsp90. The lead compounds were subjected to the Lipinski rule of five to evaluate their drug-likeness. Three-Dimensional Quantitative Structure-Activity Relationships (3D-QSAR), a mathematical model for the inhibition of Hsp90, was also derived. The lead compounds are guaiol from Cannabis sativa, actinidine from Anacadium occidentale, and choline from Tinospora cordifolia with docking scores of -11kcal/mol, -12.1kcal/mol, and -10.8kcal/mol, respectively. The 3D-QSAR model generated is robust and thoroughly validated with a correlation coefficient R of 0.94 and R2 of 0.950. Actinidine, choline and, guaiol are novel and potent inhibitors of Hsp90. They form interactions with key amino acid residues within the Hsp90 orthosteric site.


Blood ◽  
2017 ◽  
Vol 129 (5) ◽  
pp. 598-608 ◽  
Author(s):  
Roland Walter ◽  
Kuan-Ting Pan ◽  
Carmen Doebele ◽  
Federico Comoglio ◽  
Katarzyna Tomska ◽  
...  

Key Points HSP90 inhibition induces apoptosis in BL cells by disrupting tonic BCR signaling. SYK is an HSP90 client protein, and BCR signaling-dependent phosphorylation of HSP90 on Y197 is required for this interaction.


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