A fungal prion is a
prion that infects
fungal
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from th ...
hosts. Fungal prions are naturally occurring
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s that can switch between multiple, structurally distinct conformations, at least one of which is self-propagating and transmissible to other prions. This transmission of protein state represents an
epigenetic phenomenon where information is encoded in the protein structure itself, instead of in nucleic acids. Several prion-forming proteins have been identified in fungi, primarily in the yeast ''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have b ...
''. These fungal prions are generally considered benign, and in some cases even confer a selectable advantage to the organism.
Fungal prions have provided a model for the understanding of disease-forming
mammalian prions. Study of fungal prions has led to a characterisation of the sequence features and mechanisms that enable prion domains to switch between functional and amyloid-forming states.
Sequence features
Prions are formed by portable, transmissible prion domains that are often enriched in asparagine, glutamine, tyrosine and glycine residues. When a reporter protein is fused with a prion domain, it forms a chimeric protein that demonstrates the conformational switching that is characteristic of prions. Meanwhile, removing this prion domain prevents prionogenesis. This suggests that these prion domains are, in fact, portable and are the sole initiator of prionogenesis. This supports the protein-only hypothesis.
A recent study of candidate prion domains in ''S. cerevisiae'' found several specific sequence features that were common to proteins showing aggregation and self-templating properties. For example, proteins that aggregated had candidate prion domains that were more highly enriched in asparagine, while non-aggregating domains where more highly enriched in glutamine and charged peptides. There was also evidence that the spacing of charged peptides that prevent amyloid formation, such as proline, is important in prionogenesis. This discovery of sequence specificity was a departure from previous work that had suggested that the only determining factor in prionogenesis was the overall distribution of peptides.
HET-s prion of ''Podospora anserina''
''
Podospora anserina
''Podospora anserina'' is a filamentous ascomycete fungus from the order Sordariales. It is considered a model organism for the study of molecular biology of senescence (aging), prions, sexual reproduction, and meiotic drive. It has an obligat ...
'' is a filamentous fungus.
Gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
tically compatible colonies of this fungus can merge and share cellular contents such as
nutrients and
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
. A natural system of protective "incompatibility" proteins exists to prevent promiscuous sharing between unrelated colonies. One such protein, called
HET-s, adopts a prion-like form in order to function properly. The prion form of HET-s spreads rapidly throughout the cellular network of a colony and can convert the non-prion form of the protein to a prion state after compatible colonies have merged. However, when an incompatible colony tries to merge with a prion-containing colony, the prion causes the "invader" cells to die, ensuring that only related colonies obtain the benefit of sharing resources.
Prions of yeast
SI+and RE3/h2>
In 1965, Brian Cox, a geneticist working with the
yeast
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constit ...
''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have b ...
'', described a
genetic trait (termed
SI+ with an unusual pattern of
inheritance
Inheritance is the practice of receiving private property, titles, debts, entitlements, privileges, rights, and obligations upon the death of an individual. The rules of inheritance differ among societies and have changed over time. Officia ...
. The initial discovery of
SI+was made in a strain
auxotrophic
Auxotrophy ( grc, αὐξάνω "to increase"; ''τροφή'' "nourishment") is the inability of an organism to synthesize a particular organic compound required for its growth (as defined by IUPAC). An auxotroph is an organism that displays this ...
for
adenine
Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deri ...
due to a nonsense mutation. Despite many years of effort, Cox could not identify a conventional
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
that was responsible for the
SI+trait. In 1994, yeast geneticist
Reed Wickner correctly hypothesized that
SI+as well as another mysterious heritable trait,
RE3 resulted from prion forms of the normal
cellular protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respond ...
s,
Sup35p
Sup35p is the ''Saccharomyces cerevisiae'' (a yeast) eukaryotic translation release factor. More specifically, it is the yeast eukaryotic release factor 3 (eRF3), which forms the translation termination complex with eRF1 ( Sup45p in yeast). This c ...
and
Ure2p
Ure2p is a yeast protein that represses transcription of genes involved in nitrogen catabolism. It specifically regulates the utilization of poor nitrogen sources in the presence of preferred nutrients such as ammonia or glutamine. Ure2p is one ...
, respectively. The names of yeast prions are frequently placed within brackets to indicate that they are non-mendelian in their passage to progeny cells, much like plasmid and mitochondrial DNA.
Further investigation found that
SI+is the result of a self-propagating misfolded form of
Sup35p
Sup35p is the ''Saccharomyces cerevisiae'' (a yeast) eukaryotic translation release factor. More specifically, it is the yeast eukaryotic release factor 3 (eRF3), which forms the translation termination complex with eRF1 ( Sup45p in yeast). This c ...
(a 201 amino acid long protein), which is an important factor for translation termination during
protein synthesis.
In
SI+yeast cells the Sup35 protein forms filamentous aggregates known as
amyloid
Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the huma ...
. The amyloid conformation is self-propagating and represents the prion state. Amazingly distinct prion states exist for the Sup35 protein with distinct properties and these distinctions are self-propagating.
[ ] Other prions also can form distinct different variants (or strains).
It is believed that suppression of nonsense mutations in
SI+cells is due to a reduced amount of functional Sup35 because much of the protein is in the amyloid state. The Sup35 protein assembles into amyloid via an amino-terminal prion domain. The structure is based on the stacking of the prion domains in an in-register and parallel beta sheet conformation.
An important finding by Chernoff, in a collaboration between the Liebman and Lindquist laboratories, was that a
protein chaperone was required for
SI+to be maintained.
[ ] Because the only function of chaperones is to help proteins fold properly, this finding strongly supported Wickner's hypothesis that
SI+was a heritable protein state (i.e. a prion). Likewise, this finding also provided evidence for the general hypothesis that prions, including the originally proposed mammalian
PrP prion, are heritable forms of protein. Because of the action of chaperones, especially Hsp104, proteins that code for
SI+and
RE3can convert from non-prion to prion forms. For this reason, yeast prions are good models for studying factors like chaperones that affect protein aggregation.
[ ] Also, the
IPOD is the sub-cellular site to which amyloidogenic proteins are sequestered in yeast, and where prions like
SI+may undergo maturation.
Thus, prions also serve as substrates to understand the intracellular processing of protein aggregates such as amyloid.
Laboratories commonly identify
SI+by growth of a strain auxotrophic for adenine on media lacking adenine, similar to that used by Cox et al. These strains cannot synthesize adenine due to a nonsense mutation in one of the enzymes involved in the biosynthetic pathway. When the strain is grown on yeast-extract/dextrose/peptone media (YPD), the blocked pathway results in buildup of a red-colored intermediate compound, which is exported from the cell due to its toxicity. Hence, color is an alternative method of identifying
SI+--
SI+strains are white or pinkish in color, and
si-strains are red. A third method of identifying
SI+is by the presence of Sup35 in the pelleted fraction of cellular lysate.
When exposed to certain adverse conditions, in some genetic backgrounds
SI+cells actually fare better than their prion-free siblings; this finding suggests that the ability to adopt a
SI+prion form may result from positive
evolutionary selection. It has been speculated that the ability to convert between prion-infected and prion-free forms acts as an
evolutionary capacitor to enable yeast to quickly and reversibly adapt in variable environments. Nevertheless,
Reed Wickner maintains that
RE3and
SI+are diseases, although this claim has been challenged using theoretical
population genetic
Population genetics is a subfield of genetics that deals with genetic differences within and between populations, and is a part of evolutionary biology. Studies in this branch of biology examine such phenomena as adaptation, speciation, and popu ...
models.
IN+
IN, In or in may refer to:
Places
* India (country code IN)
* Indiana, United States (postal code IN)
* Ingolstadt, Germany (license plate code IN)
* In, Russia, a town in the Jewish Autonomous Oblast
Businesses and organizations
* Indepen ...
/
NQ+/h2>
The term
IN+
IN, In or in may refer to:
Places
* India (country code IN)
* Indiana, United States (postal code IN)
* Ingolstadt, Germany (license plate code IN)
* In, Russia, a town in the Jewish Autonomous Oblast
Businesses and organizations
* Indepen ...
was coined by Liebman and colleagues from Psi-INducibility, to describe a genetic requirement for the formation of the
SI+prion.
[ ] They showed that
IN+
IN, In or in may refer to:
Places
* India (country code IN)
* Indiana, United States (postal code IN)
* Ingolstadt, Germany (license plate code IN)
* In, Russia, a town in the Jewish Autonomous Oblast
Businesses and organizations
* Indepen ...
was required for the induction of most variants of the
SI+prion. Later they identified
IN+
IN, In or in may refer to:
Places
* India (country code IN)
* Indiana, United States (postal code IN)
* Ingolstadt, Germany (license plate code IN)
* In, Russia, a town in the Jewish Autonomous Oblast
Businesses and organizations
* Indepen ...
as the prion form of the RNQ1 protein
[ ][ ][ ] The more precise name
NQ+is now sometimes used because other factors or prions can also have a Psi-inducing phenotype.
A non-prion function of Rnq1 has not been definitively characterized. Though reasons for this are poorly understood, it is suggested that
IN+
IN, In or in may refer to:
Places
* India (country code IN)
* Indiana, United States (postal code IN)
* Ingolstadt, Germany (license plate code IN)
* In, Russia, a town in the Jewish Autonomous Oblast
Businesses and organizations
* Indepen ...
aggregates may act as "seeds" for the polymerization of
SI+and other prions.
[ ][ ] The basis of the
IN+
IN, In or in may refer to:
Places
* India (country code IN)
* Indiana, United States (postal code IN)
* Ingolstadt, Germany (license plate code IN)
* In, Russia, a town in the Jewish Autonomous Oblast
Businesses and organizations
* Indepen ...
prion is an amyloid form of Rnq1 arranged in in-register parallel beta sheets, like the amyloid form of Sup35. Due to similar amyloid structures, the
IN+
IN, In or in may refer to:
Places
* India (country code IN)
* Indiana, United States (postal code IN)
* Ingolstadt, Germany (license plate code IN)
* In, Russia, a town in the Jewish Autonomous Oblast
Businesses and organizations
* Indepen ...
prion may facilitate the formation of
SI+through a templating mechanism.
Two modified versions of Sup35 have been created that can induce PSI+ in the absence of
IN+
IN, In or in may refer to:
Places
* India (country code IN)
* Indiana, United States (postal code IN)
* Ingolstadt, Germany (license plate code IN)
* In, Russia, a town in the Jewish Autonomous Oblast
Businesses and organizations
* Indepen ...
when overexpressed. One version was created by digestion of the gene with the
restriction enzyme
A restriction enzyme, restriction endonuclease, REase, ENase or'' restrictase '' is an enzyme that cleaves DNA into fragments at or near specific recognition sites within molecules known as restriction sites. Restriction enzymes are one class o ...
Bal2, which results in a protein consisting of only the M and N portions of Sup35.
The other is a fusion of Sup35NM with HPR, a human membrane receptor protein.
Epigenetics
Prions act as an alternative form of non-Mendelian, phenotypic inheritance due to their self-templating ability. This makes prions a metastable, dominant mechanism for inheritance that relies solely on the conformation of the protein. Many proteins containing prion domains play a role in gene expression or RNA binding, which is how an alternative conformation can give rise to phenotypic variation. For example, the
si-state of Sup35 in yeast is a translation termination factor. When Sup35 undergoes a conformational change to the
SI+prion state, it forms amyloid fibrils and is sequestered, leading to more frequent stop codon read-through and the development of novel phenotypes. With over 20 prion-like domains identified in yeast, this gives rise to the opportunity for a significant amount of variation from a single proteome. It has been posited that this increased variation gives a selectable advantage to a population of genetically homogeneous yeast.
List of characterized prions
">The original paper that proposed Mca1 is a prion was retracted
See also
*
Prion
*
Sup35p
Sup35p is the ''Saccharomyces cerevisiae'' (a yeast) eukaryotic translation release factor. More specifically, it is the yeast eukaryotic release factor 3 (eRF3), which forms the translation termination complex with eRF1 ( Sup45p in yeast). This c ...
*
Epigenetics
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...
*
Amyloid
Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the huma ...
*
Proteopathy
In medicine, proteinopathy (; 'pref''. protein -pathy 'suff''. disease proteinopathies ''pl''.; proteinopathic ''adj''), or proteopathy, protein conformational disorder, or protein misfolding disease refers to a class of diseases in which certa ...
*
JUNQ and IPOD
JUNQ and IPOD are types of cytosolic protein inclusion bodies in eukaryotes.
Neurodegenerative diseases, such as Parkinson's, Alzheimer's, and Huntington's, are associated and correlated with protein aggregation and accumulation of misfolded ...
References
{{DEFAULTSORT:Fungal Prions
Prions
Fungal proteins