Increased Aggregation Tendency of Alpha-Synuclein in a Fully Disordered Protein Complex

Merle, David A.; Witternigg, Anja; Tam‐Amersdorfer, Carmen; Hartlmüller, Christoph; Spreitzer, Emil; Schrank, Evelyne; Wagner-Lichtenegger, Sabine; Werzer, Oliver; Zangger, Klaus; Kungl, Andreas J.; Madl, Tobias; Meyer, N. Helge; Falsone, S. Fabio

doi:10.1016/j.jmb.2019.04.031

Cited by 22 publications

(52 citation statements)

References 46 publications

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“…Note that NMR data for human SERF1a and α-synuclein also characterize the interaction of these proteins as a random fuzzy complex (32). Our data expand on this report, as we not only show complexes with multiple conformations but in multiple stoichiometries.…”

Section: Discussionsupporting

confidence: 82%

“…Another difference from polyions is that ScSERF does not integrate into fibrils, although it does have the ability to reversibly bind to preformed Aβ40 and α-synuclein fibrils. In SH-SY5Y neuroblastoma cells, ScSERF was found to colocalize with aggregated puncta of α-synuclein, indicating that this binding could also take place in vivo (32).…”

Section: Discussionmentioning

confidence: 92%

“…Merle et al (32) found that human SERF1a colocalizes with puncta of α-synuclein in human SH-SY5Y neuroblastoma cell experiments. Our observations that ScSERF can reversibly associate with preformed fibrils without integrating into their structures is consistent with these in vivo results.…”

Section: Resultsmentioning

confidence: 99%

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SERF engages in a fuzzy complex that accelerates primary nucleation of amyloid proteins

Meinen

Gadkari

Stull

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The assembly of small disordered proteins into highly ordered amyloid fibrils in Alzheimer’s and Parkinson’s patients is closely associated with dementia and neurodegeneration. Understanding the process of amyloid formation is thus crucial in the development of effective treatments for these devastating neurodegenerative diseases. Recently, a tiny, highly conserved and disordered protein called SERF was discovered to modify amyloid formation in Caenorhabditis elegans and humans. Here, we use kinetics measurements and native ion mobility-mass spectrometry to show that SERF mainly affects the rate of primary nucleation in amyloid formation for the disease-related proteins Aβ40 and α-synuclein. SERF’s high degree of plasticity enables it to bind various conformations of monomeric Aβ40 and α-synuclein to form structurally diverse, fuzzy complexes. This structural diversity persists into early stages of amyloid formation. Our results suggest that amyloid nucleation is considerably more complex than age-related conversion of Aβ40 and α-synuclein into single amyloid-prone conformations.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 92%

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SERF engages in a fuzzy complex that accelerates primary nucleation of amyloid proteins

Meinen

Gadkari

Stull

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…MOAG-4/SERF1A is involved early on in the aggregation process. In the case of alpha-synuclein, MOAG-4 and SERF hinder intermolecular interactions within the protein, through electrostatic interactions (11,14). This results in a more aggregation-prone conformation of alpha-synuclein, which in turn seeds the formation of amyloid fibrils that can eventually form large, insoluble aggregates (11,13,14).…”

Section: Introductionmentioning

confidence: 99%

“…In the case of alpha-synuclein, MOAG-4 and SERF hinder intermolecular interactions within the protein, through electrostatic interactions (11,14). This results in a more aggregation-prone conformation of alpha-synuclein, which in turn seeds the formation of amyloid fibrils that can eventually form large, insoluble aggregates (11,13,14). In addition, previous studies have shown that MOAG-4 and SERF1A act transiently and are not incorporated in amyloid fibrils themselves (11,13).…”

Section: Introductionmentioning

confidence: 99%

The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation

Pras

Houben

Aprile

et al. 2020

Preprint

Self Cite

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While aggregation-prone proteins are known to accelerate ageing and cause age-related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG-4, SERF1A and SERF2 have recently been identified as cellular modifiers of such cytotoxicity. Using a peptide array screening approach on human amyloidogenic proteins, we found that SERF2 interacted with specific patterns of negatively charged and hydrophobic, aromatic amino acids. The absence of such patterns, or the neutralization of the positive charge in SERF2, prevented these interactions and abolished the amyloid-promoting activity of SERF2. In a protein aggregation model in the nematode C. elegans, protein aggregation was suppressed by mutating the endogenous locus of MOAG-4 to neutralize charge. Our data indicate that charge interactions are required for MOAG-4 and SERF2 to promote aggregation. Such charged interactions might accelerate the primary nucleation of amyloid by initiating structural changes and by decreasing colloidal stability. Our finding that negatively charged segments are overrepresented in amyloid-forming proteins suggests that inhibition of charge interactions deserves exploration as a strategy to target age-related protein toxicity.Significance StatementHow aging causes relatively common diseases such as Alzheimer’s and Parkinson’s is still a mystery. Since toxic structural changes in proteins are likely to be responsible, we investigated biological mechanisms that could drive such changes. We made use of a modifying factor called SERF2, which accelerates structural changes and aggregation of several disease-related proteins. Through a peptide-binding screen, we found that SERF2 acts on negatively charged protein regions. The abundance of such regions in the disease-related proteins explains why SERF has its effect. Removing positive charge in SERF was sufficient to suppress protein aggregation in models for disease. We propose that blocking charge-interactions with SERF or other modifiers could serve as a general approach to treat age-related protein toxicity.

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A tale of dual functions of SERF family proteins in regulating amyloid formation

Qi,

Peng,

Wang

et al. 2024

ChemBioChem

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The abnormal aggregation of proteins is a significant pathological hallmark of diseases, such as the amyloid formation associated with fused in sarcoma protein (FUS) in frontotemporal lobar degeneration and amyotrophic lateral sclerosis diseases. Understanding which cellular components and how these components regulate the process of abnormal protein aggregation in living organisms is crucial for the prevention and treatment of neurodegenerative diseases. MOAG‐4/SERF is a conserved family of proteins with rich positive charged residues, which was initially identified as an enhancer for the formation of amyloids in C. elegans. Knocking out SERF impedes the amyloid formation of various proteins, including α‐synuclein and β‐amyloid, which are linked to Parkinson's and Alzheimer's diseases, respectively. However, recent studies revealed SERF exhibited dual functions, as it could both promote and inhibit the fibril formation of the neurodegenerative disease‐related amyloidogenic proteins. The connection between functions and structure basis of SERF in regulating the amyloid formation is still unclear. This review will outline the hallmark proteins in neurodegenerative diseases, summarize the contradictory role of the SERF protein family in promoting and inhibiting the aggregation of neurodegenerative proteins, and finally explore the potential structural basis and functional selectivity of the SERF protein.

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Increased Aggregation Tendency of Alpha-Synuclein in a Fully Disordered Protein Complex

Cited by 22 publications

References 46 publications

SERF engages in a fuzzy complex that accelerates primary nucleation of amyloid proteins

SERF engages in a fuzzy complex that accelerates primary nucleation of amyloid proteins

The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation

A tale of dual functions of SERF family proteins in regulating amyloid formation

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