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Get a Back-bone!

Kathy

Well-known member
This paper just came out from the University of California, Davis.

Researchers used computer modelling of the healthy prion protein to determine some interesting findings. When the back-bone of the prion protein contains copper, it cannot form the beta-strand back-bone identified in the mal-formed prion.


Biophys J. 2006 May 12; [Epub ahead of print] free full text article at www.biophysj.org

A mechanism for copper inhibition of infectious prion conversion.

Cox DL, Pan J, Singh RR.

UC Davis.

We employ ab initio electronic structure calculations to obtain two structural models for copper bound in the strongest binding site of the noninfectious form of the prion protein. The models are compatible with available experimental constraints from electron spin resonance data. The bending of the peptide backbone attendant with the copper binding is not compatible with the requisite straight beta-strand backbone structure for the same sequence contained in two recently proposed models of the prion protein structure in its infectious form. We hypothesize that copper binding at this site is protective against conversion to the infectious form, discuss experimental data which appear to support and conflict with our hypothesis, and propose tests using recombinant prion protein, genetically modified cultured neurons, and transgenic mice.

PMID: 16698781


This compliments Dr. DR Brown's work on copper binding to the healthy prion protein, wherein he identified locations, other than the octameric repeat region, where copper preferentially binds (if it is available). Note, he used two different techniques to confirm his findings.

J Biol Chem. 2005 Dec 30;280(52):42750-8. Epub 2005 Oct 28.

High affinity binding between copper and full-length prion protein identified by two different techniques.

Thompsett AR, Abdelraheim SR, Daniels M, Brown DR.

Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom.

The cellular prion protein is known to be a copper-binding protein. Despite the wide range of studies on the copper binding of PrP, there have been no studies to determine the affinity of the protein on both full-length prion protein and under physiological conditions. We have used two techniques, isothermal titration calorimetry and competitive metal capture analysis, to determine the affinity of copper for wild type mouse PrP and a series of mutants. High affinity copper binding by wild type PrP has been confirmed by the independent techniques indicating the presence of specific tight copper binding sites up to femtomolar affinity. Altogether, four high affinity binding sites of between femto- and nanomolar affinities are located within the octameric repeat region of the protein at physiological pH. A fifth copper binding site of lower affinity than those of the octameric repeat region has been detected in full-length protein. Binding to this site is modulated by the histidine at residue 111. Removal of the octameric repeats leads to the enhancement of affinity of this fifth site and a second binding site outside of the repeat region undetected in the wild type protein. High affinity copper binding allows PrP to compete effectively for copper in the extracellular milieu. The copper binding affinities of PrP have been compared with those of proteins of known function and are of magnitudes compatible with an extracellular copper buffer or an enzymatic function such as superoxide dismutase like activity.

PMID: 16258172
 

Econ101

Well-known member
Interesting, Kathy.

Does this mean that if you suck on an old penny you are protected?

I think they have a long way to go down this road.

I had two cousins that had muscular dystrophe. They knew the particular protein that was missing that caused them both to die at a young age after many years of muscle decline. The problem was how do you fix the condition. I know it may take some time for this research, if applicable, to do any good. My cousins waited a lifetime for their "cure". I don't think it is here yet, despite all the heroic efforts by many, many, people.
 

Kathy

Well-known member
Econo, wouldn't it be nice to have prevented the disease in the first place?

There are researchers who look at treatments once the disease has struck, and those that look at preventative measures. Of course, one must identify the problem; otherwise the treatments are just shots in the dark or lucky guesses.

This is a long road, but every journey begins with one step, and continues one step at a time.

By understanding what causes the proteins to misfold, and identifying the metal or element which is replacing copper on the prion protein - there is hope that complexes can be identified which would remove the unwanted component, and replenish the copper, or remove the malformed protein.

Like alot of diseases, once the symptoms have progressed, there are secondary effects which result from the initial break-down. Many medications/treatments only deal with those secondary break-down.

The paper mentions how acidic conditions in the body result in copper chelation from proteins. Reducing our body's acidity is a common known health factor which helps alleviate many problems.

Excess sulphur intake/exposure would increase tissue acidity, and should be examined as a precondition to TSEs. The Univ of Alberta identified (over 17 years ago) that sulphur accumulates in the brain. Dietary exposure in feedlots or dairies must be carefully monitored as there are many, many sources of sulphur besides feed - like water, air quality (including manure gases and sour gas flaring).

PEM (polioencephalomalacia) is identified as a disease which is extremely similar to BSE. Vets are instructed to attempt to differentiate PEM from BSE; but, that can be pretty tricky. PEM could easily be a co-factor for TSEs. It is becoming increasingly clear that factors which influence copper absorption are directly related to the malformed prion protein.

I suggest you supplement your diet with copper pills. The penny has very little copper in it anymore, and it might not be bio-available;)
 

Econ101

Well-known member
I said an old penny. They have all the copper in them.

I am not discounting your study, Kathy, the jury is still out on bse. Studies that prove or disprove are all important to finding the cause. They are all pieces of the puzzle.

Right now, we know that the likely transmission and amplification is through MBM. I don't want the focus of that to go away until we know what we need to know.

More studies are definitely needed. Studies such as this may have faster animal trials, that was my only meaning on the copper penny thing, it was not a "slam".
 

Kathy

Well-known member
No harm Econo.

Still there is more and more research being done on the copper and manganese properties of prions (healthy and mal-formed):

Biochemistry. 2006 May 30;45(21):6674-80.

Effect of copper and manganese on the de novo generation of protease-resistant prion protein in yeast cells.

Treiber C, Simons A, Multhaup G.

Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, Thielallee 63, D-14195 Berlin, Germany.

The prion protein (PrP) is the key protein implicated in diseases known as transmissible spongiform encephalopathies. PrP has been shown to bind manganese and copper, the latter being involved in the normal function of the protein. Indeed, upon expression in yeast we noted a major increase in intracellular copper and a decrease in manganese. Interestingly, protease-resistant PrP(Sc)-like protein (PrP(res)) formation was induced when PrP-expressing yeast cells were grown in copper- and/or manganese-supplemented media. The pattern of PrP banding in SDS-PAGE was dominantly determined by manganese. This conformational transition was stable against EDTA treatment but not in the presence of the copper chelators bathocuproinedisulfonic acid or clioquinol. Conclusively, PrP itself influences manganese and copper metabolism, and a replacement of copper in PrP complexes with manganese is highly likely under the condition of copper depletion or if excess amounts of copper and manganese are present. Taken together, our present study demonstrates the involvement of PrP in the regulation of intracellular metal ion homeostasis and uncovers copper and, more severely, manganese ions as in vivo risk factors for the conversion into PrP(Sc).

PMID: 16716078

This amazing study was actually conducted on cow brain material, wow!

Neurotoxicology. 2006 May;27(3):437-44. Epub 2006 Feb 14.

Free radical generation of protease-resistant prion after substitution of manganese for copper in bovine brain homogenate.

Deloncle R, Guillard O, Bind JL, Delaval J, Fleury N, Mauco G, Lesage G.

Universite Francois Rabelais de Tours, Bio-Inorganic Chemistry Laboratory, Faculty of Pharmacy, 31 Avenue Monge, 37200 Tours, France.

The exchange between copper and seven transition metals is studied in a bovine brain obex homogenate according to the redox status of the medium. In reductive conditions, almost all the studied metals can substitute for copper when it is in the reduced form Cu(+). This substitution is reversible, since copper uptake as Cu(++) is restored in an oxidizing medium but only Co(++), Ni(++) and Mn(++), in this decreasing order, can substitute perfectly for copper in bovine brain homogenate. To study free radical effects on bovine brain proteins, at first a copper substitution was processed in order to inhibit superoxide dismutase-like protective properties against free radicals in copper metalloproteins. Manganese was selected since a brain copper decrease correlated with a manganese increase is well-known in transmissible spongiform encephalopathies. Results for bovine brain homogenate, initially negative in the Western blot Prionics((R)) test, indicate that the substitution of manganese for copper in a reducing medium and exposure to UVA-induced free radicals produce proteinase K resistant prion. These findings suggest that an impairment in brain metal homeostasis leading to oxidative abnormalities may be involved in transmissible spongiform encephalopathies.

PMID: 16481041
 

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