Mutations in HspB1 and hereditary neuropathies
| Autor: | Sergei V. Strelkov, Lydia K. Muranova, Maria V. Sudnitsyna, Nikolai B. Gusev |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Low protein animal structures Mutant PERSPECTIVES ON sHSPs Biochemistry Protein–protein interaction 03 medical and health sciences 0302 clinical medicine Protein Domains Charcot-Marie-Tooth Disease Heat shock protein Humans Protein phosphorylation HSP20 Heat-Shock Proteins Cytoskeleton Intermediate filament Heat-Shock Proteins Motor Neurons Chemistry Cell Biology Phenotype Cell biology 030104 developmental biology Astrocytes Mutation Proteostasis 030217 neurology & neurosurgery Molecular Chaperones |
| Zdroj: | Cell Stress Chaperones |
| ISSN: | 1466-1268 |
| Popis: | Charcot-Marie-Tooth (CMT) disease is major hereditary neuropathy. CMT has been linked to mutations in a range of proteins, including the small heat shock protein HspB1. Here we review the properties of several HspB1 mutants associated with CMT. In vitro, mutations in the N-terminal domain lead to a formation of larger HspB1 oligomers when compared with the wild-type (WT) protein. These mutants are resistant to phosphorylation-induced dissociation and reveal lower chaperone-like activity than the WT on a range of model substrates. Mutations in the α-crystallin domain lead to the formation of yet larger HspB1 oligomers tending to dissociate at low protein concentration and having variable chaperone-like activity. Mutations in the conservative IPV motif within the C-terminal domain induce the formation of very large oligomers with low chaperone-like activity. Most mutants interact with a partner small heat shock protein, HspB6, in a manner different from that of the WT protein. The link between the altered physico-chemical properties and the pathological CMT phenotype is a subject of discussion. Certain HspB1 mutations appear to have an effect on cytoskeletal elements such as intermediate filaments and/or microtubules, and by this means damage the axonal transport. In addition, mutations of HspB1 can affect the metabolism in astroglia and indirectly modulate the viability of motor neurons. While the mechanisms of pathological mutations in HspB1 are likely to vary greatly across different mutations, further in vitro and in vivo studies are required for a better understanding of the CMT disease at molecular level. |
| Databáze: | OpenAIRE |
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