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U.S. study boosts prion theory for mad cow disease
Support for the Prion Hypothesis in Yeast
Yeast prions: commentary
Prion-Inducing Domain of Yeast Ure2p and Protease Resistance
Heat-shock protein 104 and nonsense suppression by yeast prion PSI+
Similarity of yeast Sup35p and Ure2p proteins to mammalian prions
Chaperone protein Hsp104 and yeast prion-like factor [psi+]
Amino Acid Sequence of Yeast prion PSI+
Amino Acid Sequence of Yeast prion Ure2
Amino Acid Sequence of Human prion - octapeptide repeats


U.S. study boosts prion theory for mad cow disease

Evans, Eddie ... 8.1.96 ... (Reuter)

WASHINGTON - Research published this week adds weight to the theory that the mysterious prion protein is behind mad cow disease and other degenerative brain disorders such as Creutzfeldt- Jakob Disease in people. Proteins with defective traits similar to the prions thought to cause mad cow disease were capable of passing on their defects to proteins in neighboring cells, an article in Friday's issue of the journal Science said. Whether prions were capable of "infecting" other proteins has been a major argument between supporters of the prion hypothesis and researchers who say viruses cause the brain-wasting diseases.

"This validates the concept of the prion in mammals," said geneticist Susan Lindquist of the research she carried out with colleagues at the University of Chicago. Lindquist, who used a prion-like yeast protein, told Reuters the finding made the mechanism by which the prion was thought to destroy the brain more believable. "It's a plausible mechanism now. If you can see it working in yeast it makes it seem plausible that it could work in other proteins, " she said. She said she believed the deformed protein "cozied up" to proteins in other cells, forcing them to adopt the same deformed shape. The effect would be eventually to destroy the cell and neighboring cells, causing the sponge-like holes in the brain that have given mad cow disease its formal name -- Bovine Spongiform Encephalopathy (BSE).

In the new research, deformed yeast proteins were shown to clump together while normal ones would be evenly spread. This was further evidence of the prion mechanism, Lindquist said. It was the first time characteristics of proteins have been shown to pass from one protein to another without any DNA undergoing any change or serving as the blueprint for change. "It's genetics without DNA," Lindquist said. "We think this is a mechanism of inheritance that people haven't realized existed."

DNA, or deoxyribonucleic acid, is the material in each cell that contains the genetic blueprints for life. The prion hypothesis for mad cow disease, Creutzfeldt-Jakob and the cannibal disease kuru has existed for 30 years, since researchers showed that diseased brain tissue remained infectious even after heat treatment that would have destroyed any DNA. The British government set off a scare over mad cow disease in March when it announced there may be a link between the disease and a new variant of Creutzfeldt-Jakob Disease, suggesting that humans were at risk from the mad cow epidemic.


Support for the Prion Hypothesis in Yeast

Maria M. Patino, Jia-Jia Liu, John R. Glover, Susan Lindquist August 2, 1996 Science

A cytoplasmically inherited genetic element in yeast, [PSI+], was confirmed to be a prionlike aggregate of the cellular protein Sup35 by differential centrifugation analysis and microscopic localization of a Sup35--green fluorescent protein fusion. Aggregation depended on the intracellular concentration and functional state of the chaperone protein Hsp104 in the same manner as did [PSI+] inheritance. The amino-terminal and carboxy-terminal domains of Sup35 contributed to the unusual behavior of [PSI+].

[PSI+] altered the conformational state of newly synthesized prion proteins, inducing them to aggregate as well, thus fulfilling a major tenet of the prion hypothesis.


Yeast prions

Volume 270, Number 5233, Issue of 6 October 1995, p. 9
This Week in SCIENCE: Commentary

Prions--a type of infectious protein responsible for causing several neurodegenerative disorders in mammals--have recently been identified in yeast. Masison and Wickner (p. 93) now show that the propagation of the prion phenotype in yeast requires a specific domain of the prion precursor protein, Ure2p, which normally plays a role in controlling nitrogen catabolism. After induction of the prion phenotype, it becomes resistant to proteolysis. The prion-inducing domain could be deleted from Ure2p, which left the nitrogen control function intact but abolished the susceptibility of the yeast cells to express the prion phenotype.


Prion-Inducing Domain of Yeast Ure2p and Protease Resistance

Science Volume 270, Number 5233, Issue of 6 October 1995, pp. 93-95
Daniel C. Masison and Reed B. Wickner

The genetic properties of the [URE3] non-Mendelian element of Saccharomyces cerevisiae suggest that it is a prion (infectious protein) form of Ure2p, a regulator of nitrogen catabolism. In extracts from [URE3] strains, Ure2p was partially resistant to proteinase K compared with Ure2p from wild-type extracts. Overexpression of Ure2p in wild-type strains induced a 20- to 200-fold increase in the frequency with which [URE3] arose. Overexpression of just the amino-terminal 65 residues of Ure2p increased the frequency of [URE3] induction 6000-fold.

Without this ``prion-inducing domain'' the carboxyl-terminal domain performed the nitrogen regulation function of Ure2p, but could not be changed to the [URE3] prion state. Thus, this domain induced the prion state in trans, whereas in cis it conferred susceptibility of the adjoining nitrogen regulatory domain to prion infections.


Heat-shock protein 104 expression is sufficient for thermo-tolerance in yeast

Lindquist S; Kim G
Proc Natl Acad Sci U S A 93: 5301-6 (1996)

In all organisms, mild heat pretreatments induce tolerance to high temperatures. In yeast such pretreatments strongly induce heat-shock protein (Hsp) 104, and hsp104 mutations greatly reduce high-temperature survival, indicating Hsp1O4 plays a critical role in induced thermotolerance. Expression of heat-shock factor (and the viability of the strain) requires nonsense suppression mediated by the yeast prion [PSI+]. We conclude that Hsp1O4 plays a central role in ameliorating heat toxicity. Because Hsp1O4 is nontoxic and highly conserved, manipulating the expression of Hsp1OO proteins provides an excellent prospect for manipulating thermotolerance in other species.


Structure and functional similarity of yeast Sup35p and Ure2p proteins to mammalian prions
Kushnirov VV; Ter-Avanesian MD; Smirnov VN
Mol Biol (Mosk) 29: 750-5 (1995) [in Russian]

The existence of tandem amino acid repeats in N-terminal regions of yeast Sup35p protein and in prions of higher eukaryotes is shown. The prion-like properties of yeast Sup35p and Ure2p proteins and a role of tandem amino acid repeats localized in N-terminal region of Sup35p protein in inheritance of [psi] determinants is discussed. The suggestion is made that the [psi+] status of yeast cell depends on the specific conformation of the N-terminal domain of Sup35p and that this protein can induce the specific conformational state of its N-terminal domain on newly synthesized Sup35p molecules via protein-protein interaction, thus representing a molecular basis of inheritance of [psi+] determinant. Other proteins containing amino acid repeats of similar type are considered and the suggestion is made that some of these proteins may show prion-like behavior.


Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]

Chernoff YO; Lindquist SL; Ono B; Inge-Vechtomov SG; Liebman SW
Science 268: 880-4 (1995)

The yeast non-Mendelian factor [psi+] has been suggested to be a self-modified protein analogous to mammalian prions. Here it is reported that an intermediate amount of the chaperone protein Hsp104 was required for the propagation of the [psi+] factor. Over-production or inactivation of Hsp104 caused the loss of [psi+]. These results suggest that chaperone proteins play a role in prion-like phenomena, and that a certain level of chaperone expression can cure cells of prions without affecting viability. This may lead to anti-prion treatments that involve the alteration of chaperone amounts or activity.


Amino Acid Sequence of Yeast prion PSI+
 MSDSNQGNNQQNYQQYSQNGNQQQGNNRYQGYQAYNAQAQPAGG
                     YYQNYQGYSGYQQGGYQQYNPDAGYQQQYNPQGGYQQYNPQGGYQQQFNPQGGRGNYK
                     NFNYNNNLQGYQAGFQPQSQGMSLNDFQKQQKQAAPKPKKTLKLVSSSGIKLANATKK
                     VGTKPAESDKKEEEKSAETKEPTKEPTKVEEPVKKEEKPVQTEEKTEEKSELPKVEDL
                     KISESTHNTNNANVTSADALIKEQEEEVDDEVVNDMFGGKDHVSLIFMGHVDAGKSTM
                     GGNLLYLTGSVDKRTIEKYEREAKDAGRQGWYLSWVMDTNKEERNDGKTIEVGKAYFE
                     TEKRRYTILDAPGHKMYVSEMIGGASQADVGVLVISARKGEYETGFERGGQTREHALL
                     AKTQGVNKMVVVVNKMDDPTVNWSKERYDQCVSNVSNFLRAIGYNIKTDVVFMPVSGY
                     SGANLKDHVDPKECPWYTGPTLLEYLDTMNHVDRHINAPFMLPIAAKMKDLGTIVEGK
                     IESGHIKKGQSTLLMPNKTAVEIQNIYNETENEVDMAMCGEQVKLRIKGVEEEDISPG
                     FVLTSPKNPIKSVTKFVAQIAIVELKSIIAAGFSCVMHVHTAIEEVHIVKLLHKLEKG
                     TNRKSKKPPAFAKKGMKVIAVLETEAPVCVETYQDYPQLGRFTLRDQGTTIAIGKIVK
                     IAE

Amino Acid Sequence of Yeast prion URE2 The URE2 gene product of Saccharomyces cerevisiae plays an important role in the cellular response to the nitrogen source and has homology to glutathione s-transferases

Mol. Cell. Biol. 11, 822-832 (1991)

  MMNNNGNQVSNLSNALRQVNIGNRNSNTTTDQSNINFEFSTGVN
                     NNNNNNSSSNNNNVQNNNSGRNGSQNNDNENNIKNTLEQHRQQQQAFSDMSHVEYSRI
                     TKFFQEQPLEGYTLFSHRSAPNGFKVAIVLSELGFHYNTIFLDFNLGEHRAPEFVSVN
                     PNARVPALIDHGMDNLSIWESGAILLHLVNKYYKETGNPLLWSDDLADQSQINAWLFF
                     QTSGHAPMIGQALHFRYFHSQKIASAVERYTDEVRRVYGVVEMALAERREALVMELDT
                     ENAAAYSAGTTPMSQSRFFDYPVWLVGDKLTIADLAFVPWNNVVDRIGINIKIEFPEV
                     YKWTKHMMRRPAVIKALRGE

Amino Acid Sequence of Human prion
 MANLGCWMLVLFVATWSDLGLCKKRPKPGGWNTGGSRYPGQGSP
                     GGNRYPPQGGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQGGGTHSQWNKP
                     SKPKTNMKHMAGAAAAGAVVGGLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQ
                     VYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQY
                     ERESQAYYQRGSSMVLFSSPPVILLISFLIFLIVG
Octapeptide repeating unit: WGQPHGGG