Structural Fuzziness of the RNA-Organizing Protein SERF Determines a Toxic Gain-of-interaction

Meyer, N. Helge; Dellago, Hanna; Tam‐Amersdorfer, Carmen; Merle, David A.; Parlato, Rosanna; Gesslbauer, Bernd; Almer, Johannes; Gschwandtner, Martha; León, Ana Gloria Vázquez de; Franzmann, Titus M.; Grillari, Johannes; Kungl, Andreas J.; Zangger, Klaus; Falsone, S. Fabio

doi:10.1016/j.jmb.2019.11.014

Cited by 23 publications

(55 citation statements)

References 64 publications

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“…Of these proteins, 19 are amyloidogenic (15) ( Table S1, column A). Four of these amyloidogenic proteins have previously been shown to functionally interact with SERF (Table S1, proteins marked in bold) (12)(13)(14)16). The other proteins represented on the slide included three other disease-related aggregation-prone proteins, four disease-related dipeptide repeat polymers, a protein for which amyloid formation is part of its physiological function and four non-amyloidogenic proteins (Table S1, columns B, C, D).…”

Section: Serf2 Selectively Binds To Negatively Charged Peptidesmentioning

confidence: 99%

“…SERF2 is a highly positively charged protein that has a net charge of +10, mainly due to a region in its N-terminus that is evolutionarily highly conserved ( Figure S2A and S2B). To assess the role of this region in the charge-based interactions between SERF2 and amyloidogenic proteins, we neutralized the net charge of +5 in this region by inducing point mutations in the three positively charged amino acids, Lys 16 , Lys 17 and Lys 23 ( Figure 4A). To exclude the possibility of the charge mutations resulting in structural changes relative to the wild-type protein, the secondary structure of both proteins was assessed with Fouriertransform infrared spectroscopy (FTIR, Figure S2C).…”

Section: The Positively Charged N-terminus Of Serf2 Mediates Bindingmentioning

confidence: 99%

“…Our data indicates that the positive charge in the N-terminus of SERF2 is required for interactions with amyloidogenic proteins and for subsequent acceleration of amyloid formation. To confirm that it is indeed the positively charged nature of Lys 16 , Lys 17 and Lys 23 in SERF2 that is responsible for this ability and not any other lysine-specific characteristic, we created a lysine-to-arginine SERF2 mutant (KR-mutant, Figure 7A Figure 7B, 7C and 7D). These data support our hypothesis that charge complementation drives the interactions between SERF2 and substrate proteins, and indicates that no property of lysine, other than its positive charge is required for these interactions.…”

Section: Charge Rather Than Amino-acid Composition Of Moag-4/serf Drimentioning

confidence: 99%

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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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Section: Serf2 Selectively Binds To Negatively Charged Peptidesmentioning

confidence: 99%

Section: The Positively Charged N-terminus Of Serf2 Mediates Bindingmentioning

confidence: 99%

Section: Charge Rather Than Amino-acid Composition Of Moag-4/serf Drimentioning

confidence: 99%

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

Pras

Houben

Aprile

et al. 2020

Preprint

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“…Upon binding to their partners, intrinsically disordered proteins span a continuum in the extent of structuredness, from fully folded to partially ordered to fully disordered. The "extreme" fuzzy complexes in the latter case have been characterized when the partners are another disordered protein or a nucleic acid [1][2][3][4][5] . A third class of partners for disordered proteins comprise membranes [6][7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

“…Many disordered proteins are enriched in charged residues 11 , and interactions between opposite charged residues are crucial features of extreme fuzzy complexes between disordered proteins 1,2 . Likewise the interactions between basic residues of proteins and acidic phosphate groups of nucleic acids are crucial for their high-affinity, fuzzy association [3][4][5] . The inner leaflet of the plasma membrane is highly acidic, due to asymmetric distribution of charged lipids including phosphatidylserine, phosphatidylinositol, and the latter's phosphorylated variants 12 , and thus forms a target for polybasic proteins including signaling molecules 7 .…”

Section: Introductionmentioning

confidence: 99%

Extreme Fuzzy Association of an Intrinsically Disordered Protein with Acidic Membranes

Hicks

Escobar

Cross

et al. 2020

Preprint

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Many physiological and pathophysiological processes, including Mycobacterium tuberculosis (Mtb) cell division, may involve fuzzy membrane association by proteins via intrinsically disordered regions. The fuzziness is extreme when the conformation and pose of the bound protein and the composition of the proximal lipids are all highly dynamic. Here we tackled the challenge in characterizing the extreme fuzzy membrane association of the disordered, cytoplasmic N-terminal region (NT) of ChiZ, an Mtb divisome protein, by combining solution and solid-state NMR spectroscopy and molecular dynamics simulations. In a typical pose, NT is anchored to acidic membranes by Arg residues in the midsection. Competition for Arg interactions between lipids and acidic residues, all in the first half of NT, makes the second half more prominent in membrane association. This asymmetry is accentuated by membrane tethering of the downstream transmembrane helix. These insights into sequence-interaction relations may serve as a paradigm for understanding fuzzy membrane association.

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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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Structural Fuzziness of the RNA-Organizing Protein SERF Determines a Toxic Gain-of-interaction

Cited by 23 publications

References 64 publications

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

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

Extreme Fuzzy Association of an Intrinsically Disordered Protein with Acidic Membranes

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

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