The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors
| Autor: | Yi-Wei Chang, Edward B. Lee, Benjamin C Creekmore |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Aging
Proteasome Endopeptidase Complex Valosin-containing protein macromolecular substances Protein aggregation Pathology and Forensic Medicine Protein Aggregates 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Ubiquitin medicine Humans Review Articles 030304 developmental biology 0303 health sciences biology Cryoelectron Microscopy Neurodegeneration Neurodegenerative Diseases General Medicine medicine.disease AAA proteins Cell biology Proteostasis Neurology Structural biology Proteasome biology.protein Neurology (clinical) 030217 neurology & neurosurgery |
| Zdroj: | J Neuropathol Exp Neurol |
| ISSN: | 1554-6578 0022-3069 |
| DOI: | 10.1093/jnen/nlab029 |
| Popis: | Neurodegenerative diseases are characterized by the accumulation of misfolded proteins. This protein aggregation suggests that abnormal proteostasis contributes to aging-related neurodegeneration. A better fundamental understanding of proteins that regulate proteostasis may provide insight into the pathophysiology of neurodegenerative disease and may perhaps reveal novel therapeutic opportunities. The 26S proteasome is the key effector of the ubiquitin-proteasome system responsible for degrading polyubiquitinated proteins. However, additional factors, such as valosin-containing protein (VCP/p97/Cdc48) and C9orf72, play a role in regulation and trafficking of substrates through the normal proteostasis systems of a cell. Nonhuman AAA+ ATPases, such as the disaggregase Hsp104, also provide insights into the biochemical processes that regulate protein aggregation. X-ray crystallography and cryo-electron microscopy (cryo-EM) structures not bound to substrate have provided meaningful information about the 26S proteasome, VCP, and Hsp104. However, recent cryo-EM structures bound to substrate have provided new information about the function and mechanism of these proteostasis factors. Cryo-EM and cryo-electron tomography data combined with biochemical data have also increased the understanding of C9orf72 and its role in maintaining proteostasis. These structural insights provide a foundation for understanding proteostasis mechanisms with near-atomic resolution upon which insights can be gleaned regarding the pathophysiology of neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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