BIOCHEMISTRY
Small and commonly
Fatal structural changes of proteins

Prions call the strange proteins which can change into dangerous illness causes. However, not only with Cow?s Delusion and company, also with other neuro-degenerative illnesses misfolded proteins play a bad role.

The whirl has lain down. However, for the science prion, that "protein-like infectious particle" which have moved the meat consumer into fear and fright are still a subject. Even if the heretical idea of the Nobel Prize Laureate Stanley Prusiner that proteins without nucleic acid can increase and release illnesses is accepted to a great extent, nobody knows exactly, why harmless egg white molecules can pull such fatal consequences like cattle insanity and Creutzfeldt Jakob-Illness after themselves.

Is only known that there are two forms of a prion protein (PrP): As soon as the harmless variation - we call them PrP-sen - is confronted with her bad sister called PrP-res, she changes for their part into the PrP-res variation which can rush at new PrP-sen forms. A chain reaction with which fibrous protein clusters originate and which - if she runs off not in the test tube, but in the brain - fatally ends.

Whether the resulted protein fibers release the destructions in the brain immediately, or whether they are only one concomitant of prion illnesses, nobody also knows. Many doctors still pursue the idea to stop the chain, while they try to dissolve the got lumpy protein fibers again. However, this way could cause exactly the opposite, think the researchers around Jay Silveira [1].

The scientists of the Rocky Mountain labs of the Nationwide institutes of Allergy and Infectious Diseases have closer looked with hamsters which prion particle are infectious. And surprises the result. Since these were not the long protein fibers well visible in the microscope which turned out dangerous. Rather the very small Prion aggregates which existed merely of 14 to 28 molecules appeared substantially more infectious than the long chains. Only the aggregates which existed of less than five unities remained harmless. Now becomes - with which means also always - tries to crack the prion fibers and to open in smaller unities, originate precisely the highly infectious particle, warn the researchers.

Yet how does it come generally in addition that proteins convert in an autocatalytic process even into a new structure with new qualities? In the end, that contradicts a central dogma of the protein chemistry which biochemist Christian Anfinsen has put up fifty years ago in laborious work: The sequence determines the conformation. In other words: Only the order of the stones, the amino acid sequence, fixes which spatial figure will take a protein as the energetically most favorable state.

Now the scientists around Shilpa Sambashivan of the university of California in Los Angeles tried to trick Anfinsen?s hypothesis - namely exactly with that protein for whose structural clarification Anfinsen had got in 1972 the chemistry Nobel Prize: ribonuclease [2].

The researchers managed with briefly RNase A called protein a small, but deciding change: On position 112 they inserted a short piece with ten molecules of the amino acid glutamine. Thereby received the protein whose structure is stabilized by disulfide bridges, a kind of joint with which the gigantic molecule can be opened. Thermo-dynamically the closed form remains the stable variation, however, now and again will open one or other of the changed RNase molecules. If one end of an open molecule settles now by chance to the other end of the second open RNase, there originates a short chain, - and this is the exciting - thermo-dynamically again is stable. Therefore, the balance is shifted in the direction of chain, more and more open RNase are taken up, the chain grows like from only further.

And exactly after this principle prion or also other protein structures, as for example the infamous Alzheimer-Plaques, to her dangerous aggregated form - with the known consequences could do itself.

Andreas Jahn

STREAM:
[1] Nature 437: 257-261 (2005)
[2] Nature 437: 266-269 (2005)

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