A new study shows that CHIP can regulate insulin receptors more efficiently than in the dual state. In cases of cellular stress, CHIP typically appears as a homodimer – the union of two identical proteins – and primarily serves to break down defective and damaged proteins. Thus, the cell chip is cleaned. To this end, CHIP cooperates with the helper proteins to link a chain of the ubiquitin small protein to the misfolded proteins. Thus the defective proteins are recognized and eliminated by the cell. In addition, CHIP also regulates insulin receptor signal transduction. CHIP binds ubiquitin to the receptor to break it down and deactivate life-prolonging gene products.
A research team in Cologne led by Professor Dr. Thorsten Hoebe has now demonstrated in experiments with the nematode Caenorhabditis elegans and human cells CHIP can also call itself ubiquitin, which prevents the formation of its dimers. The CHIP monomer is more efficient than the dimer in regulating insulin signaling. The study by the University of Cologne Excellence Group of Cellular Stress Responses in Diseases Associated with Aging (CECAD) was published in molecular cell Titled “A Dimer-Monomer Switch Controls Chip-Based Substrate Use and Manipulation.”
“Whether CHIP acts alone or as a pair depends on the state of the cell. Under stress, there are too many denatured proteins as well as helper proteins that bind to CHIP and inhibit self-proliferation, and self-labelling with ubiquitin,” said Vishnu Balaji, first author of the study.
“After CHIP has successfully scavenged the defective proteins, it can also mark the degradation co-proteins. This allows CHIP to be ubiquitous and act as a monomer again,” he explained. Thus, for the body to function smoothly, there must be a balance between the unilateral and dual states of CHIP.
“Interestingly, the monomer-dimer equilibrium of CHIP appears to be disrupted in it Neurological diseasesThorsten Hoppe said. “In cases of spinocerebellar ataxia, for example, different sites of CHIP are mutated, and act mostly in a dimer. Here, switching to more monomers would be a potential therapeutic approach.”
In the next step, the scientists want to know if there are other proteins or receptors to which the CHIP monomer binds, and thus regulates its function. Researchers are also interested in knowing which tissues, organs and diseases in which CHIP monomers or dimers occur in greater numbers, in order to be able to develop more targeted therapies in the future.
Vishnu Balaji et al, A two-monomer diffusion switch controls chip-dependent substrate diffusion and processing, molecular cell (2022). DOI: 10.1016 / j.molcel.2022.08.003
University of Cologne
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