The Dark Side of Alzheimer’s Disease: Unstructured Biology of Proteins from the Amyloid Cascade Signaling Pathway
Document Type
Article
Publication Date
2020
Keywords
Alzheimer’s disease, Amyloid cascade signaling, Intrinsically disordered proteins, Amyloid-beta, Molecular recognition features
Digital Object Identifier (DOI)
https://doi.org/10.1007/s00018-019-03414-9
Abstract
Alzheimer’s disease (AD) is a leading cause of age-related dementia worldwide. Despite more than a century of intensive research, we are not anywhere near the discovery of a cure for this disease or a way to prevent its progression. Among the various molecular mechanisms proposed for the description of the pathogenesis and progression of AD, the amyloid cascade hypothesis, according to which accumulation of a product of amyloid precursor protein (APP) cleavage, amyloid β (Aβ) peptide, induces pathological changes in the brain observed in AD, occupies a unique niche. Although multiple proteins have been implicated in this amyloid cascade signaling pathway, their structure–function relationships are mostly unexplored. However, it is known that two major proteins related to AD pathology, Aβ peptide, and microtubule-associated protein tau belong to the category of intrinsically disordered proteins (IDPs), which are the functionally important proteins characterized by a lack of fixed, ordered three-dimensional structure. IDPs and intrinsically disordered protein regions (IDPRs) play numerous vital roles in various cellular processes, such as signaling, cell cycle regulation, macromolecular recognition, and promiscuous binding. However, the deregulation and misfolding of IDPs may lead to disturbed signaling, interactions, and disease pathogenesis. Often, molecular recognition-related IDPs/IDPRs undergo disorder-to-order transition upon binding to their biological partners and contain specific disorder-based binding motifs, known as molecular recognition features (MoRFs). Knowing the intrinsic disorder status and disorder-based functionality of proteins associated with amyloid cascade signaling pathway may help to untangle the mechanisms of AD pathogenesis and help identify therapeutic targets. In this paper, we have used multiple computational tools to evaluate the presence of intrinsic disorder and MoRFs in 27 proteins potentially relevant to the amyloid cascade signaling pathway. Among these, BIN1, APP, APOE, PICALM, PSEN1 and CD33 were found to be highly disordered. Furthermore, their disorder-based binding regions and associated short linear motifs have also been identified. These findings represent important foundation for the future research, and experimental characterization of disordered regions in these proteins is required to better understand their roles in AD pathogenesis.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Cellular and Molecular Life Sciences, v. 77, p. 4163-4208
Scholar Commons Citation
Gadhave, Kundlik; Gehi, Bhuvaneshwari R.; Kumar, Prateek; Xue, Bin; Uversky, Vladimir N.; and Giri, Rajanish, "The Dark Side of Alzheimer’s Disease: Unstructured Biology of Proteins from the Amyloid Cascade Signaling Pathway" (2020). Molecular Medicine Faculty Publications. 183.
https://digitalcommons.usf.edu/mme_facpub/183
