prions are infectious proteins , able to propagate and transmit the infection from one individual to another without an essential nucleic acid .
in addition to this horizontal transmission , typical of the mammalian transmissible spongiform encephalopathies ( tses ) , prions of fungi also transmit the infection vertically ( to their offspring ) , and so they are proteins acting as genes , just as nucleic acids can act as enzymes ( table 1 ) .
prions of mammals , yeast and the filamentous fungus podospora anserina most prions are amyloids  filamentous polymers high in -sheet structure , usually protease resistant and with characteristic staining properties .
prion transmission occurs when donor amyloid enters the recipient cell and the equivalent recipient protein joins to the ends of the amyloid filaments , which act as a structural template , so that the recipient protein adopts ( usually ) the same conformation as the donor amyloid .
the known prion - forming proteins of yeast and mammals are listed in table 1 .
a single prion protein sequence can form any of several biologically distinct prion ' strains ' or ' variants ' , differentiated in mammals by incubation time , disease signs and lesion distribution , or in yeast by prion stability , phenotype intensity or sensitivity to elevated or depressed levels of particular chaperones ( reviewed in ) .
different prion variants have different amyloid structures , although the exact structures are as yet unknown .
prions that are fully infectious between individuals of the same mammalian or yeast species may transmit poorly  or not at all  between species , a phenomenon called the species barrier . in spite of centuries of exposure ,
sheep scrapie is not known to have been transmitted to humans , but bovine spongiform encephalopathy ( bse ) has ( fortunately only rarely ) done so .
the primary determinants of the species barrier are the sequences of the potential prion proteins of the two species . however , the prion variant is also an important factor .
for example , the ure2 nitrogen regulation proteins of various saccharomyces species can become prions ( called [ ure3 ] ) , and species barriers are seen among these [ ure3]s that are dependent on the prion variant . while one variant of the [ ure3 ] prion of species a may transmit with 100% efficiency to species b , another variant may transmit with 0% efficiency between the same two species .
these phenomena can be explained by assuming that each sequence has a range of possible conformers .
a narrow overlap of conformers between donor and recipient produces a high species barrier , while a wide overlap implies a low barrier .
thus , according to this model , a specific conformer common to donor and recipient could overcome what would otherwise be a high species barrier .
it is likely that interactions with chaperones or other cellular factors , known to differ depending on prion variant , will be found to be at least part of some species barriers . in yeast ,
de novo formation of prions can , though rarely , be primed by other prions .
all of the prion - forming proteins of yeast have asparagine / glutamine - rich prion domains , and this shared structure is thought to enable prions of one of the proteins to prime filament formation by others .
in fact , de novo generation of the [ psi ] prion of saccharomyces cerevisiae is almost undetectable in a strain not carrying one of the other prions .
this cross - seeding produces an array of prion variants , whereas passing a species barrier usually produces a single , unchanged prion variant in the recipient . in both mammals and yeast ,
if a prion is successfully transmitted to a new host , the variant produced in the recipient is usually that of the donor .
for example , when zoo animals were infected with bse , and those infections were then introduced into mice , the same unique distribution of brain lesions was seen as when mice were infected with bse directly from cows .
similarly , passing the [ ure3 ] of one species through ure2p of a different species and then returning it to the original ure2p generally produces a [ ure3 ] prion 1 with the same properties as the original . in some cases ,
however , infection of a new species is so inefficient  in other words , the species barrier is so high  that disease only results if a ' mutant ' prion is selected that can replicate readily in the new host ( figure 1a ) .
for example , mouse scrapie strain 139a only produces disease in hamsters after an extended incubation period ( see , for example ) .
serial passage of the infection in hamsters then eventually produced a shorter stable incubation period .
however , on passage from hamsters back into mice and after the initial species barrier had subsided by a few passages , the agent had a dramatically longer incubation period than the original mouse scrapie and gave a different brain - lesion profile .
the conclusion from this classic experiment was that a ' mutant ' scrapie strain had been selected .
( a ) an altered form ( a ' mutant ' ) of mouse scrapie strain 139a is selected by the high species barrier encountered when it is transferred to hamsters ( modified from ) .
( b ) the species barrier between the s. cerevisiae sup 35 prion [ psi ] and a chimeric protein with a p. methanolica sup35 prion domain results in the rare generation of either of two [ chipm ] prion variants of the latter on exposure to [ psi ] .
( c ) schematic diagram showing partial templating by species a amyloid filament of species b protein .
species b protein sequence is incompatible with all of species a filament structure , and so assumes an altered self - propagating form  a prion variant .
an apparently analogous phenomenon has recently been reported in bmc biology by vishveshwara and liebman using chimeric yeast prions .
the [ psi ] prion of s. cerevisiae is based on an amyloid form of the protein sup35p , which normally functions as a translation termination factor ( table 1 ) .
sup35p has a glutamine ( q)/asparagine ( n)-rich amino - terminal prion domain ( n )  the domain responsible for amyloid formation  a charged middle domain ( m ) , and a carboxy - terminal domain ( c ) , which is responsible for sup35p 's normal function of translation termination . a chimeric protein made by fusing the similarly q / n - rich n domain and the m domain of sup35 protein of the yeast pichia methanolica to the s. cerevisiae c domain ( nmpm - csc )
will act as a prion , called [ chipm ] , when expressed in s. cerevisiae .
however , the considerable sequence difference between the p. methanolica and s. cerevisiae sup35 n domains results in a species barrier between the two n domains , so that prion transmission is rare . moreover , the rare prion transmission from [ psi ] to [ chipm ] results in at least two different prion variants of the chimera ( figure 1b ) .
this indicates that the s. cerevisiae sup35n amyloid was not able to accurately template the chimera , although its presence certainly induced prion formation by the chimeric protein . in this case , it was probably prion generation that was induced by [ psi ] , rather than transmission , although it remains possible that one of the [ chipm ] variants corresponds to the original [ psi ] variant .
the similarity between the scrapie ' mutation ' phenomenon and the yeast stimulated prion generation is striking . in each case , sequence differences largely blocked duplication of the donor prion conformation , resulting in only partial templating and generation of altered prion variants .
this also is presumed to be the basis of the prion priming phenomenon described above .
the structure of infectious prp is not yet known , but infectious amyloids of the prion domains of ure2p , sup35p and rnq1p each have an in - register parallel -sheet structure ( see , for example , ) .
thus , each residue of the last monomer to join the filament contacts the same residue of the preceding monomer ( figure 1c ) .
the register is maintained by hydrogen bonds between gln or asn ( the so - called -zipper ) and possibly between ser and thr residues .
a line of hydrophobic residues down the fiber will likewise have positive interactions , helping to keep the -sheet in register .
the location of turns , the contacts between -sheets and the extent of -sheet are thus transmitted to the newly joined monomer . combined with chain breakage to make new seeds ,
a weakly homologous or non - homologous ( but still q / n rich ) monomer might interact with part of the monomer on the end of the filament , so that only part of its conformation was fixed .
the remainder may form by some stochastic interaction with another monomer identical to itself ( shown schematically in figure 1c ) .
this could explain yeast prion cross - seeding and the ' mutation ' phenomena using the known structural information .
unlike the mammalian tses and the yeast prions [ ure3 ] and [ psi ] , which are all diseases , the [ het - s ] prion of the filamentous fungus podospora anserina is evolved to be a prion .
it appears to function for the host in hetero - karyon incompatibility , and to be the basis of a striking meiotic drive phenomenon . which is the phenomenon and which is the ' epiphenomenon ' is not yet clear , but in either case , the het - s protein is evolved to be a prion .
only a single prion variant of [ het - s ] has been described , as would be expected for a protein evolved to be a prion .
the infectivity and heritability of yeast prions and the ease of yeast manipulation as exemplified by the work of vishveshwara and liebman   make possible detailed studies of different amyloid forms , their generation and interaction with each other and with other cellular components , that would be impossible in the non - infectious amyloid diseases of mammals .
nonetheless , the findings with the prions are applicable to the non - infectious amyloid diseases that pose a burgeoning problem for our aging populations . both the cross - seeding phenomenon , as suggested by the coincident occurrence of amyloids of a peptide , tau , -synuclein and others in the human amyloidoses , and the variant phenomenon , as in the different self - propagating amyloid forms of a , are apparently present in non - infectious amyloidoses .
this work was supported by the intramural program of the national institute of diabetes digestive and kidney diseases . due to journal policy
, we have only sparingly referenced the literature and apologize to those whose work we were unable to specifically mention .
 prion variants faithfully propagate across species barriers , but if the barrier is too high , new variants ( mutants ) are selected , as shown in a recent bmc biology report 
 . protein sequence alteration can prevent accurate structural templating at filament ends producing prion variants . 
None
Crossing the species barrier
Prion cross-seeding
What is the structural basis of variant phenomena?
A prion without variants is evolved to be a prion: [Het-s]
Acknowledgements