Structural Insights into Functional and Pathological Amyloid

Shewmaker, Frank; McGlinchey, Ryan P.; Wickner, Reed B.

doi:10.1074/jbc.r111.227108

Cited by 154 publications

(166 citation statements)

References 100 publications

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“…While most amyloid structures determined to date have demonstrated a parallel arrangement of monomers (39)(40)(41), important characteristics of these functional hydrophobin rodlets support the antiparallel arrangement presented in this model. Critically, the antiparallel arrangement of monomers maintains the dimensions and amphipathic nature of the rodlet monolayer that is characteristic of these fungal assemblies and fundamental to their biological functions.…”

Section: Discussionsupporting

confidence: 52%

Self-assembly of functional, amphipathic amyloid monolayers by the fungal hydrophobin EAS

Macindoe

Kwan

Ren

et al. 2012

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

121

111

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The hydrophobin EAS from the fungus Neurospora crassa forms functional amyloid fibrils called rodlets that facilitate spore formation and dispersal. Self-assembly of EAS into fibrillar rodlets occurs spontaneously at hydrophobic:hydrophilic interfaces and the rodlets further associate laterally to form amphipathic monolayers. We have used site-directed mutagenesis and peptide experiments to identify the region of EAS that drives intermolecular association and formation of the cross-β rodlet structure. Transplanting this region into a nonamyloidogenic hydrophobin enables it to form rodlets. We have also determined the structure and dynamics of an EAS variant with reduced rodlet-forming ability. Taken together, these data allow us to pinpoint the conformational changes that take place when hydrophobins self-assemble at an interface and to propose a model for the amphipathic EAS rodlet structure.A myloid fibrils were first identified in association with human diseases, but recent discoveries show that the amyloid ultrastructure also contributes to important functions in normal biology (1, 2). In bacteria, fungi, insects, fish, and mammals, amyloid structures perform a wide variety of roles (3). Functional amyloids in the form of fibrillar rodlets composed of class I hydrophobin proteins are found in filamentous fungi. These hydrophobins are small proteins that are secreted as monomers and self-assemble into rodlets that pack to form amphipathic monolayers at hydrophilic: hydrophobic boundaries, such as the surface of the growth medium (4). These proteins are extremely surface active and lower the surface tension of the aqueous growth medium, allowing hyphae to break through the surface and to produce aerial structures (5, 6). Many of these aerial structures subsequently become coated with amyloid rodlets, creating a hydrophobic layer that serves multiple purposes, including conferring water resistance to spores for easier dispersal in air (7), preventing wetting or collapse of gas transfer channels (8), enhancing adherence to waxy surfaces such as leaves during infection of rice plants by Magnaporthe grisea (9), and mediating evasion of the immune system as is observed in Aspergillus fumigatus infections (10).Hydrophobins are characterized by the presence of eight cysteine residues that form four disulphide bonds, but the hydrophobin family can be further divided into two classes based on the spacing of the conserved cysteine residues and the nature of the amphipathic monolayers that they form (11). Class I, but not class II, hydrophobins form amyloid-like rodlets that are extremely robust and require treatment with strong acid to induce depolymerization. The amphipathic monolayers formed by class II hydrophobins are not fibrillar and can be dissociated by treatment with detergent and alcohol solutions. The soluble, monomeric forms of hydrophobins share a unique β-barrel topology, and all have a relatively large exposed hydrophobic area on the protein monomer surface (4). The diversity in sequence and chain length ...

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Section: Discussionsupporting

confidence: 52%

Self-assembly of functional, amphipathic amyloid monolayers by the fungal hydrophobin EAS

Macindoe

Kwan

Ren

et al. 2012

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

121

111

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“…Although amyloid fibrils are typically associated with pathology, some amyloid fibrils perform biological functions. For instance, amyloid fibril formation by a domain of Pmel17 plays a role in melanin polymerization in animal cells, and some spider silk fibers consist of amyloid fibrils formed from spidroin (Chiti and Dobson 2006;Hammer et al 2008;Shewmaker et al 2011). Amyloid fibril formation has been shown for numerous proteins under the appropriate conditions; however, not all of these proteins are considered prion-like (Bucciantini et al 2002).…”

Section: How Would the Amyloid Aggregation Of P53 Contribute To Oncogmentioning

confidence: 99%

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

Costa

Oliveira

Cino

et al. 2016

Cold Spring Harb Perspect Biol

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Prion diseases are disorders that share several characteristics that are typical of many neurodegenerative diseases. Recently, several studies have extended the prion concept to pathological aggregation in malignant tumors involving misfolded p53, a tumor-suppressor protein. The aggregation of p53 and its coaggregation with p53 family members, p63 and p73, have been shown. Certain p53 mutants exert a dominant-negative regulatory effect on wild-type (WT) p53. The basis for this dominant-negative effect is that amyloid-like mutant p53 converts WT p53 into an aggregated species, leading to a gain-of-function (GoF) phenotype and the loss of its tumor-suppressor function. Recently, it was shown that p53 aggregates can be internalized by cells and can coaggregate with endogenous p53, corroborating the prion-like properties of p53 aggregates. The prion-like behavior of oncogenic p53 mutants provides an explanation for its dominant-negative and GoF properties, including the high metastatic potential of cancer cells carrying p53 mutations. The inhibition of p53 aggregation appears to represent a promising target for therapeutic intervention in patients with malignant tumors.

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“…Most prions are self-propagating amyloids, linear filamentous polymers of a single protein. The prions [PSI+], [URE3], and [PIN+] of S. cerevisiae are parallel in-register β-sheet amyloids of Sup35p, Ure2p, and Rnq1p, respectively (7)(8)(9)(10); the [Het-s] prion of P. anserina is a β-helical amyloid of the HET-s protein (11). Sup35p is a subunit of the translation termination factor (12,13), Ure2p is a regulator of nitrogen catabolism (14), and Rnq1p has no known function (15).…”

mentioning

confidence: 99%

Sex, prions, and plasmids in yeast

Kelly

Shewmaker

Kryndushkin

et al. 2012

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

Self Cite

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Even deadly prions may be widespread in nature if they spread by infection faster than they kill off their hosts. The yeast prions [PSI+] and [URE3] (amyloids of Sup35p and Ure2p) were not found in 70 wild strains, while [PIN+] (amyloid of Rnq1p) was found in ∼16% of the same population. Yeast prion infection occurs only by mating, balancing the detrimental effects of carrying the prion. We estimated the frequency of outcross mating as about 1% of mitotic doublings from the known detriment of carrying the 2-μm DNA plasmid (∼1%) and its frequency in wild populations (38/70). We also estimated the fraction of total matings that are outcross matings (∼23-46%) from the fraction of heterozygosity at the highly polymorphic RNQ1 locus (∼46% [PIN+] of S. cerevisiae are parallel in-register β-sheet amyloids of Sup35p, Ure2p, and Rnq1p, respectively (7-10); the [Het-s] prion of P. anserina is a β-helical amyloid of the HET-s protein (11). Sup35p is a subunit of the translation termination factor (12, 13), Ure2p is a regulator of nitrogen catabolism (14), and Rnq1p has no known function (15).The mammalian prions are uniformly lethal but nonetheless are found in wild animals. For example, chronic wasting disease of deer and elk is found in ∼10% of wild deer in parts of Wyoming, Colorado, Illinois, and Wisconsin (16). Evidently, infectious spread outpaces the lethal effects on the animals. The [Het-s] prion of P. anserina is involved in heterokaryon incompatibility, a normal function of that species, and, as a result, ∼80% of wild strains with the appropriate chromosomal genotype carry the [Het-s] (20), a result confirmed by others (21) and which we interpreted as meaning that they are substantially detrimental. Nonetheless, others argue that these prions are beneficial, promoting survival by allowing cells to resist stress (22, 23), although the reported effects were not reproducible with the same strains (24). It is reported further that certain stress conditions increase the frequency of[PSI+] when assayed using a synthetic Sup35p with an elevated prion-forming tendency (25). Here we test these conditions for an effect on prion formation by the wild-type Sup35p.Our argument, that the rare occurrence of an infectious agent in nature implies pathologic effects on the host, relies on outcross mating being a fairly frequent event. Yeast prions spread only by mating (there is no extracellular prion species in the replication cycle), and if outcross mating is extremely rare, then yeast prions could be rare even if their effects on the host were neutral. Yeast spores germinate with mating type either a or α, and a and α spores from the same tetrad may mate (intratetrad or brothersister). The mating-type switching system (homothallism) results in the clone from a single germinated spore becoming a mixture of a and α cells which can mate with each other. These two kinds of "selfing" are unlikely to spread any virus, plasmid, or prion, because probably both mating partners will lack the element, or both will have it. Alternat...

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Structural Insights into Functional and Pathological Amyloid

Cited by 154 publications

References 100 publications

Self-assembly of functional, amphipathic amyloid monolayers by the fungal hydrophobin EAS

Self-assembly of functional, amphipathic amyloid monolayers by the fungal hydrophobin EAS

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

Sex, prions, and plasmids in yeast

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