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

Meinen, Ben A.; Gadkari, Varun V.; Stull, Frederick; Ruotolo, Brandon T.; Bardwell, James C.A.

doi:10.1073/pnas.1913316116

Cited by 32 publications

(65 citation statements)

References 48 publications

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“…The two main influences are sequence/conformation-dependent (left-hand side) or occur as a result of binding to interaction partners (right-hand side). Ham et al, 2010;Falsone et al, 2012;Meinen et al, 2019). Although the binding site on SERF for all of these amyloidogenic proteins has yet to be identified, αSyn was shown to bind via its C-terminal region (residues 110-140) (Falsone et al, 2012).…”

Section: Flanking Regions That Protect Against Aggregationmentioning

confidence: 99%

Looking Beyond the Core: The Role of Flanking Regions in the Aggregation of Amyloidogenic Peptides and Proteins

2020

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Amyloid proteins are involved in many neurodegenerative disorders such as Alzheimer’s disease [Tau, Amyloid β (Aβ)], Parkinson’s disease [alpha-synuclein (αSyn)], and amyotrophic lateral sclerosis (TDP-43). Driven by the early observation of the presence of ordered structure within amyloid fibrils and the potential to develop inhibitors of their formation, a major goal of the amyloid field has been to elucidate the structure of the amyloid fold at atomic resolution. This has now been achieved for a wide variety of sequences using solid-state NMR, microcrystallography, X-ray fiber diffraction and cryo-electron microscopy. These studies, together with in silico methods able to predict aggregation-prone regions (APRs) in protein sequences, have provided a wealth of information about the ordered fibril cores that comprise the amyloid fold. Structural and kinetic analyses have also shown that amyloidogenic proteins often contain less well-ordered sequences outside of the amyloid core (termed here as flanking regions) that modulate function, toxicity and/or aggregation rates. These flanking regions, which often form a dynamically disordered “fuzzy coat” around the fibril core, have been shown to play key parts in the physiological roles of functional amyloids, including the binding of RNA and in phase separation. They are also the mediators of chaperone binding and membrane binding/disruption in toxic amyloid assemblies. Here, we review the role of flanking regions in different proteins spanning both functional amyloid and amyloid in disease, in the context of their role in aggregation, toxicity and cellular (dys)function. Understanding the properties of these regions could provide new opportunities to target disease-related aggregation without disturbing critical biological functions.

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Section: Flanking Regions That Protect Against Aggregationmentioning

confidence: 99%

Looking Beyond the Core: The Role of Flanking Regions in the Aggregation of Amyloidogenic Peptides and Proteins

2020

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“…The copyright holder for this preprint this version posted January 5, 2021. ; https://doi.org/10.1101/2021.01.05.423442 doi: bioRxiv preprint extended in nature 92 . For α-Syn, the disruption of intra-molecular electrostatic interactions by the positively charged region of MOAG-4/SERF1 was found to expose an amyloid nucleation site 68,95 .…”

Section: Discussionmentioning

confidence: 99%

“…The nuclei act as seeds from which the fibrils grow and have been shown to propagate a specific fibril structure(Petkova et al , 2005; Qiang et al , 2017). In vitro kinetic assays with SERF and MOAG-4 have shown that these peptides accelerate aggregation by acting on the nucleation phase(Meinen et al , 2019; Falsone et al , 2012; Yoshimura et al , 2017; Merle et al , 2019). Recently, we have shown that SERF2 is equally capable to drive amyloid formation of α-Syn and Aβ in vitro through a conserved, positively charged region(Pras et al , 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we have shown that SERF2 is equally capable to drive amyloid formation of α-Syn and Aβ in vitro through a conserved, positively charged region(Pras et al , 2020). Meanwhile, another study has demonstrated that binding of the intrinsically disordered protein yeast SERF to α-Syn and Aβ results in fuzzy complexes with heterogeneous structural conformations that are more extended in nature(Meinen et al , 2019). For α-Syn, the disruption of intra-molecular electrostatic interactions by the positively charged region of MOAG-4/SERF1 was found to expose an amyloid nucleation site(Merle et al , 2019; Yoshimura et al , 2017).…”

Section: Discussionmentioning

confidence: 99%

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SERF deletion modifies amyloid aggregation in a mouse model of Alzheimer’s disease

Stroo

Janssen

Sin

et al. 2021

Preprint

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Neurodegenerative diseases like Alzheimer, Parkinson and Huntington disease are characterized by aggregation-prone proteins that form amyloid fibrils through a nucleation process. Despite the shared β-sheet structure, recent research has shown that structurally different polymorphs exist within fibrils of the same protein. These polymorphs are associated with varying levels of toxicity and different disease phenotypes. MOAG-4 and its human orthologs SERF1 and SERF2 have previously been shown to modify the nucleation and drive amyloid formation and protein toxicity in vitro and in C. elegans. To further explore these findings, we generated a Serf2 knockout (KO) mouse model and crossed it with the APPPS1 mouse model for Aβ amyloid pathology. Full-body KO of Serf2 resulted in a developmental delay and perinatal lethality due to insufficient lung maturation. Therefore, we proceeded with a brain-specific Serf2 KO, which was found to be viable. We examined the Aβ pathology at 1 and 3 months of age, which is before and after the start of amyloid deposition. We show that SERF2 deficiency does not affect the production and overall Aβ levels. Serf2 KO-APPPS1 mice displayed an increased intracellular Aβ accumulation at 1 month and a higher number of Aβ deposits compared to APPPS1 mice with similar Aβ levels. Moreover, conformation-specific dyes and electron microscopy revealed a difference in the structure and amyloid content of these Aβ deposits. Together, our results reveal that SERF2 causes a structural shift in Aβ aggregation in a mammalian brain. These findings indicate that a single endogenous factor may contribute to amyloid polymorphisms, allowing for new insights into this phenomenon’s contribution to disease manifestation.HighlightsLoss of SERF2 slows embryonic development and causes perinatal lethalitySERF2 affects proliferation in a cell-autonomous fashionBrain-specific Serf2 knockout does not affect viability or Aβ productionBrain deletion of Serf2 shifts the amyloid conformation of Aβ

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“…Interestingly, the interactions between alpha-synuclein and SERF1A or its yeast ortholog ScSERF have been shown to result in the formation of a fully disordered protein complex, which accelerates the primary nucleation of alpha-synuclein amyloid formation (14,46,47).…”

Section: Discussionmentioning

confidence: 99%

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

Pras

Houben

Aprile

et al. 2020

Preprint

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

Cited by 32 publications

References 48 publications

Looking Beyond the Core: The Role of Flanking Regions in the Aggregation of Amyloidogenic Peptides and Proteins

Looking Beyond the Core: The Role of Flanking Regions in the Aggregation of Amyloidogenic Peptides and Proteins

SERF deletion modifies amyloid aggregation in a mouse model of Alzheimer’s disease

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

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