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- Mahapatra, Sayanta, et al.
(författare)
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Substoichiometric Hsp104 regulates the genesis and persistence of self-replicable amyloid seeds of Sup35 prion domain
- 2022
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Ingår i: Journal of Biological Chemistry. - : Elsevier. - 0021-9258 .- 1083-351X. ; 298:8
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Tidskriftsartikel (refereegranskat)abstract
- Prion-like self-perpetuating conformational conversion of proteins is involved in both transmissible neurodegenerative diseases in mammals and non-Mendelian inheritance in yeast. The transmissibility of amyloid-like aggregates is dependent on the stoichiometry of chaperones such as heat shock proteins (Hsps), including disaggregases. To provide the mechanistic underpinnings of the formation and persistence of prefibrillar amyloid seeds, we investigated the role of substoichiometric Hsp104 on the in vitro amyloid aggregation of the prion domain (NM-domain) of Saccharomyces cerevisiae Sup35. At low substoichiometric concentrations, we show Hsp104 exhibits a dual role: it considerably accelerates the formation of prefibrillar species by shortening the lag phase but also prolongs their persistence by introducing unusual kinetic halts and delaying their conversion into mature amyloid fibers. Additionally, Hsp104-modulated amyloid species displayed a better seeding capability compared to NM-only amyloids. Using biochemical and biophysical tools coupled with site-specific dynamic readouts, we characterized the distinct structural and dynamical signatures of these amyloids. We reveal that Hsp104-remodeled amyloidogenic species are compositionally diverse in prefibrillar aggregates and are packed in a more ordered fashion compared to NM-only amyloids. Finally, we show these Hsp104-remodeled, conformationally distinct NM aggregates display an enhanced autocatalytic self-templating ability that might be crucial for phenotypic outcomes. Taken together, our results demonstrate that substoichiometric Hsp104 promotes compositional diversity and conformational modulations during amyloid formation, yielding effective prefibrillar seeds that are capable of driving prion-like Sup35 propagation. Our findings underscore the key functional and pathological roles of substoichiometric chaperones in prion-like propagation.
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| 2. |
- Madhu, Priyanka, et al.
(författare)
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Distinct types of amyloid-beta oligomers displaying diverse neurotoxicity mechanisms in Alzheimer's disease
- 2021
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Ingår i: Journal of Cellular Biochemistry. - : John Wiley & Sons. - 0730-2312 .- 1097-4644. ; 122:11, s. 1594-1608
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Forskningsöversikt (refereegranskat)abstract
- Soluble oligomers of amyloid-beta (A beta) are recognized as key pernicious species in Alzheimer's disease (AD) that cause synaptic dysfunction and memory impairments. Numerous studies have identified various types of A beta oligomers having heterogeneous peptide length, size distribution, structure, appearance, and toxicity. Here, we review the characteristics of soluble A beta oligomers based on their morphology, size, and structural reactivity toward the conformation-specific antibodies and then describe their formation, localization, and cellular effects in AD brains, in vivo and in vitro. We also summarize the mechanistic pathways by which these soluble A beta oligomers cause proteasomal impairment, calcium dyshomeostasis, inhibition of long-term potentiation, apoptosis, mitochondrial damage, and cognitive decline. These cellular events include three distinct molecular mechanisms: (i) high-affinity binding with the receptors for A beta oligomers such as N-methyl- d-aspartate receptors, cellular prion protein, nerve growth factor, insulin receptors, and frizzled receptors; (ii) the interaction of A beta oligomers with the lipid membranes; (iii) intraneuronal accumulation of A beta by alpha 7-nicotinic acetylcholine receptors, apolipoprotein E, and receptor for advanced glycation end products. These studies indicate that there is a pressing need to carefully examine the role of size, appearance, and the conformation of oligomers in identifying the specific mechanism of neurotoxicity that may uncover potential targets for designing AD therapeutics.
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| 3. |
- Madhu, Priyanka, et al.
(författare)
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How viral proteins bind short linear motifs and intrinsically disordered domains
- 2022
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Ingår i: Essays in Biochemistry. - : Portland Press. - 0071-1365 .- 1744-1358. ; 66:7, s. 935-944
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Forskningsöversikt (refereegranskat)abstract
- Viruses are the obligate intracellular parasites that exploit the host cellular machinery to repli-cate their genome. During the viral life cycle viruses manipulate the host cell through inter-actions with host proteins. Many of these protein-protein interactions are mediated through the recognition of host globular domains by short linear motifs (SLiMs), or longer intrinsically disordered domains (IDD), in the disordered regions of viral proteins. However, viruses also employ their own globular domains for binding to SLiMs and IDDs present in host proteins or virus proteins. In this review, we focus on the different strategies adopted by viruses to utilize proteins or protein domains for binding to the disordered regions of human or/and viral ligands. With a set of examples, we describe viral domains that bind human SLiMs. We also provide examples of viral proteins that bind to SLiMs, or IDDs, of viral proteins as a part of complex assembly and regulation of protein functions. The protein-protein interactions are often crucial for viral replication, and may thus offer possibilities for innovative inhibitor design.
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