Fungal prions
Encyclopedia
Fungal
prions provide an excellent model for the understanding of disease-forming mammal
ian prions. Fungal prions are naturally occurring proteins that can undergo a structural conversion that becomes self-propagating and infectious. They represent an epigenetic phenomenon in which information is not encoded in the nuclear DNA
, but is structurally encoded within the protein. Several prion-forming protein
s have been identified in fungi, primarily in the yeast Saccharomyces cerevisiae
. Some of these are not associated with any disease state and may possibly have a beneficial role by giving an evolution
ary advantage to their host.
tically compatible colonies of this fungus can merge together and share cellular contents such as nutrient
s and cytoplasm
. 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.
Saccharomyces cerevisiae
, described a genetic
trait
(termed [PSI+]) with an unusual pattern of inheritance. The initial discovery of [PSI+] was made in a strain auxotrophic for adenine
due to a nonsense mutation. Despite many years of effort, Cox could not identify a conventional mutation
that was responsible for the [PSI+] trait. In 1994, yeast geneticist Reed Wickner
correctly hypothesized that [PSI+] as well as another mysterious heritable trait, [URE3], resulted from prion forms of certain normal cellular proteins. 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.
It was soon noticed that heat shock protein
s (which help other proteins fold properly) such as Hsp104 were intimately tied to the inheritance and transmission of [PSI+] and many other yeast prions. Since then, researchers have unravelled how the proteins that code for [PSI+] and [URE3] can convert between prion and non-prion forms, as well as the consequences of having intracellular prions.
When exposed to certain adverse conditions, in some genetic backgrounds [PSI+] cells actually fare better than their prion-free siblings; this finding suggests that the ability to adopt a [PSI+] 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, Wickner maintains that URE3 and [PSI+] are diseases, although this claim has been challenged using theoretical population genetic models.
Further investigation found that [PSI+] is the result of a self-propagating misfolded form of Sup35p
, which is an important factor for translation termination during protein synthesis. In [PSI+] yeast cells the Sup35 protein forms filamentous aggregates known as amyloid
. The amyloid conformation is self-propagating and represents the prion state. It is believed that suppression of nonsense mutations in [PSI+] 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 confirmation.
Laboratories commonly identify [PSI+] 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 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 [PSI+] -- [PSI+] strains are white or pinkish in color, and [psi-] strains are red. A third method of identifying [PSI+] is by the presence of Sup35 in the pelleted fraction of cellular lysate.
, the basis of the [PIN+] prion is an amyloid form of Rnq1. The amyloid is composed of the Rnq1 protein arranged in in-register parallel beta sheets, like the amyloid form of Sup35. Due to similar amyloid structures, the [PIN+] prion may facilitate the formation of [PSI+] through a templating mechanism.
Two modified versions of Sup35 have been created that can induce PSI+ in the absence of [PIN+] when overexpressed. One version was created by digestion of the gene with BalI, 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.
Fungus
A fungus is a member of a large 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, Fungi, which is separate from plants, animals, and bacteria...
prions provide an excellent model for the understanding of disease-forming mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian prions. Fungal prions are naturally occurring proteins that can undergo a structural conversion that becomes self-propagating and infectious. They represent an epigenetic phenomenon in which information is not encoded in the nuclear DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, but is structurally encoded within the protein. Several prion-forming protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s have been identified in fungi, primarily in the yeast Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
. Some of these are not associated with any disease state and may possibly have a beneficial role by giving an evolution
Evolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...
ary advantage to their host.
The HET-s Prion of Podospora anserina
Podospora anserina is a filamentous fungus. GeneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
tically compatible colonies of this fungus can merge together and share cellular contents such as nutrient
Nutrient
A nutrient is a chemical that an organism needs to live and grow or a substance used in an organism's metabolism which must be taken in from its environment. They are used to build and repair tissues, regulate body processes and are converted to and used as energy...
s and cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
. 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.
[PSI+] & [URE3]
In 1965, Brian Cox, a geneticist working with the yeastYeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
, described a genetic
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
trait
Trait (biology)
A trait is a distinct variant of a phenotypic character of an organism that may be inherited, environmentally determined or be a combination of the two...
(termed [PSI+]) with an unusual pattern of inheritance. The initial discovery of [PSI+] was made in a strain auxotrophic for adenine
Adenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
due to a nonsense mutation. Despite many years of effort, Cox could not identify a conventional mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
that was responsible for the [PSI+] trait. In 1994, yeast geneticist Reed Wickner
Reed Wickner
Reed B. Wickner is an American yeast geneticist. In 1994 he proposed that the [PSI+] and [URE3] phenotypes in Saccharomyces cerevisiae, a form of budding yeast, were caused by prion forms of native proteins. Specifically, the sup35p protein....
correctly hypothesized that [PSI+] as well as another mysterious heritable trait, [URE3], resulted from prion forms of certain normal cellular proteins. 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.
It was soon noticed that heat shock protein
Heat shock protein
Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...
s (which help other proteins fold properly) such as Hsp104 were intimately tied to the inheritance and transmission of [PSI+] and many other yeast prions. Since then, researchers have unravelled how the proteins that code for [PSI+] and [URE3] can convert between prion and non-prion forms, as well as the consequences of having intracellular prions.
When exposed to certain adverse conditions, in some genetic backgrounds [PSI+] cells actually fare better than their prion-free siblings; this finding suggests that the ability to adopt a [PSI+] prion form may result from positive evolutionary selection
Natural selection
Natural selection is the nonrandom process by which biologic traits become either more or less common in a population as a function of differential reproduction of their bearers. It is a key mechanism of evolution....
. It has been speculated that the ability to convert between prion-infected and prion-free forms acts as an evolutionary capacitor
Evolutionary capacitance
Just as electric capacitors store and release charge, by analogy evolutionary capacitance is the storage and release of variation. Living systems are robust to mutations. This means that living systems accumulate genetic variation without the variation having a phenotypic effect...
to enable yeast to quickly and reversibly adapt in variable environments. Nevertheless, Wickner maintains that URE3 and [PSI+] are diseases, although this claim has been challenged using theoretical population genetic models.
Further investigation found that [PSI+] is the result of a self-propagating misfolded form of Sup35p
Sup35p
Sup35p is the Saccharomyces cerevisiae eukaryotic translation release factor. More specifically, it is the yeast eukaryotic release factor 3 , which forms the translation termination complex with eRF1 . This complex recognizes and catalyzes the release of the nascent polypeptide chain when the...
, which is an important factor for translation termination during protein synthesis. In [PSI+] yeast cells the Sup35 protein forms filamentous aggregates known as amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
. The amyloid conformation is self-propagating and represents the prion state. It is believed that suppression of nonsense mutations in [PSI+] 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 confirmation.
Laboratories commonly identify [PSI+] 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 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 [PSI+] -- [PSI+] strains are white or pinkish in color, and [psi-] strains are red. A third method of identifying [PSI+] is by the presence of Sup35 in the pelleted fraction of cellular lysate.
[PIN+]
[PIN+], in turn, is the misfolded form of the protein Rnq1. However, the normal function of this protein is unknown to date. It is of note that for the induction of most variants of [PSI+], the presence of [PIN+] is required. Though reasons for this are poorly understood, it is suggested that [PIN+] aggregates may act as “seeds” for the polymerization of [PSI+]. Like Sup35 and Ure2Ure2
Ure2 is the Saccharomyces cerevisiae inhibitor of nitrogen catabolism genes under nitrogen-rich conditions. It controls the nitrogen catabolite response by sequestering the transcription factor Gln3 in the cytoplasm and preventing it from entering the nucleus....
, the basis of the [PIN+] prion is an amyloid form of Rnq1. The amyloid is composed of the Rnq1 protein arranged in in-register parallel beta sheets, like the amyloid form of Sup35. Due to similar amyloid structures, the [PIN+] prion may facilitate the formation of [PSI+] through a templating mechanism.
Two modified versions of Sup35 have been created that can induce PSI+ in the absence of [PIN+] when overexpressed. One version was created by digestion of the gene with BalI, 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.
List of Characterized Fungal Prions
| Fungal Prions | ||||||
|---|---|---|---|---|---|---|
| Protein Protein Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of... |
Natural Host | Normal Function | Prion State | Prion Phenotype | Year Identified | |
| Ure2p 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 of the few yeast proteins that are known to be prions... |
Saccharomyces cerevisiae Saccharomyces cerevisiae Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes... |
Nitrogen catabolite repressor | [URE3] | Growth on poor nitrogen sources | 1994 | |
| Sup35p Sup35p Sup35p is the Saccharomyces cerevisiae eukaryotic translation release factor. More specifically, it is the yeast eukaryotic release factor 3 , which forms the translation termination complex with eRF1 . This complex recognizes and catalyzes the release of the nascent polypeptide chain when the... |
Saccharomyces cerevisiae Saccharomyces cerevisiae Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes... |
Translation termination factor | [PSI+] | Increased levels of nonsense suppression | 1994 | |
| HET-S | Podospora anserina | Regulates heterokaryon Heterokaryon A heterokaryon is a cell that contains multiple, genetically different nuclei. This can occur naturally, such as in the mycelium of fungi during sexual reproduction, or artificially as formed by the experimental fusion of two genetically different cells. A medical example is a heterokaryon composed... incompatibility |
[Het-s] | Heterokaryon formation between incompatible strains | ||
| Rnq1p | Saccharomyces cerevisiae Saccharomyces cerevisiae Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes... |
Protein template factor | [RNQ+],[PIN+] | Promotes aggregation of other prions | ||
| Mca1* | Saccharomyces cerevisiae Saccharomyces cerevisiae Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes... |
Putative Yeast Caspase | [MCA+] | Unknown | 2008 | |
| Swi1 | Saccharomyces cerevisiae Saccharomyces cerevisiae Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes... |
chromatin remodeling | [SWI+] | poor growth on some carbon sources | 2008 | |
| Cyc8 | Saccharomyces cerevisiae Saccharomyces cerevisiae Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes... |
transcriptional repressor | [OCT+] | transcriptional derepression of multiple genes | 2009 | |
| Mot3 | Saccharomyces cerevisiae Saccharomyces cerevisiae Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes... |
nuclear transcription factor | [MOT3+] | transcriptional derepression of anaerobic genes | 2009 | |
| Pma1 the major plasma membrane proton pump Std1 |
Saccharomyces cerevisiae Saccharomyces cerevisiae Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes... |
[GAR+] | resistant to glucose-associated repression | 2009 | ||
| Sfp1 | Saccharomyces cerevisiae Saccharomyces cerevisiae Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes... |
global transcriptional regulator | [ISP+] | antisuppressor of certain sup35 mutations | 2010 | |
- The original paper that proposed Mca1 is a prion was retracted
See also
- PrionPrionA prion is an infectious agent composed of protein in a misfolded form. This is in contrast to all other known infectious agents which must contain nucleic acids . The word prion, coined in 1982 by Stanley B. Prusiner, is a portmanteau derived from the words protein and infection...
- Sup35pSup35pSup35p is the Saccharomyces cerevisiae eukaryotic translation release factor. More specifically, it is the yeast eukaryotic release factor 3 , which forms the translation termination complex with eRF1 . This complex recognizes and catalyzes the release of the nascent polypeptide chain when the...
- EpigeneticsEpigeneticsIn biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- -genetics...
- AmyloidAmyloidAmyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
- ProteopathyProteopathyIn medicine, proteopathy refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body...