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A prion is an infectious agent composed of protein in a misfolded form. The name prion, is derived from the words protein and infectious. Prions are responsible for the transmissible spongiform encephalopathies  in mammals .In humans, prions cause [http://en.wikipedia.org/wiki/Creutzfeldt%E2%80%93Jakob_disease Creutzfeldt-Jakob Disease](CJD), [http://en.wikipedia.org/wiki/Fatal_familial_insomnia Fatal Familial Insomnia](FFI) and [http://en.wikipedia.org/wiki/Kuru_%28disease%29 kuru].
Prions, misfolded proteins, are responsible of the transmissible spongiform encephalopathy in mammals. The primitive protein is involved in the cell differentiation and adhesion. In humans, prions cause. In humans, prions cause [http://en.wikipedia.org/wiki/Creutzfeldt%E2%80%93Jakob_disease Creutzfeldt-Jakob Disease](CJD), [http://en.wikipedia.org/wiki/Fatal_familial_insomnia Fatal Familial Insomnia](FFI) and [http://en.wikipedia.org/wiki/Kuru_%28disease%29 kuru].


The 3haf structure results from a work leaded by Lee S. in 2010, in which they have characterized seven variants of the human prion. The structure was determined by XRAY diffraction in a 2.26-Angstrom resolution.
Human prion is a membrane protein of 16284.86 Da. The infectious agent penetrates the neuron and due to reasons and mechanisms still misunderstood, it multiplies, by opening/folding normal proteins in pathogenic prions. This new form cannot be degraded by proteolysis and the aggregation of misfiled proteins induces the death of cells and the accumulation of amyloid plaque in the brain.


3haf is a domain of the Major [http://en.wikipedia.org/wiki/Prion prion]protein. This domain is between the residue 120 and the 225 of the entire prion .This structure is a succession of [http://en.wikipedia.org/wiki/Alpha_helix alpha helix] and [http://en.wikipedia.org/wiki/Beta_sheet beta sheet]. The domain contains sites of [http://en.wikipedia.org/wiki/Glycosylation glycolisation]. It can be noticed a mismatch precisely at the residue 129, where a Valin substitutes a Methionin, influencing the susceptibility of the formation of the prion.
3HAF is a vaiant domain of the major [http://en.wikipedia.org/wiki/Prion prion]protein going from residue 90 to 231, which is constitute of 253 amino acids. Compare to the sequence of the major prion protein, a Valine substitutes a Methionine at the 129 residue, influencing the susceptibility of the formation of the prion.


==Structure of 3HAF domain of Human Prion==
==Structure of 3HAF domain of Human Prion==
The 3HAF structure results from a work leaded by Lee S. in 2010, in which they have characterized seven variants of the human prion. The structure was determined by XRAY diffraction in a 2.26-Angstrom resolution.


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The secondary structure is a succession of alpha helix and beta sheet:
The unique chain of 3HAF is constituted of 7 helix (Alpha helix 112-135, Alpha helix 144-153, 3/10 helix 154-156, 3/10 helix 165-169, Alpha helix 172-192, Alpha helix 194-197, Alpha helix 200-227) and of 2 beta-sheet (129-130 and 160-163).
The proportion of each structure is 43% of <scene name='56/568013/Alpha_helix/9'>Alpha Helix</scene>(7 helix, 62 residues) and 2% of <scene name='56/568013/Beta_sheet/1'>Beta Sheet</scene> (2 strands, 4 residues).


Alpha helix (112-135) _ coil_ alpha helix (144-153)_ coil_3/10 helix (165-169)_coil_ alpha helix_ coil_ alpha helix (200-227)
3 residues can have a contact with metals; S132, H140 and D147.
A lot of empty structures are present between helix.
One of the structure is called 3/10 helix (Each amino acid corresponds to a 120° turn in the helix).


The proportion of each structure is 43% of <scene name='56/568013/Alpha_helix/9'>Alpha Helix</scene> (6 helix, 62 residues) and 2% of <scene name='56/568013/Beta_sheet/1'>Beta Sheet</scene>(2 strands, 4 residues). There are also 2 glycosylation sites and the C-ter domain is higher conserved.
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* Tertiary structure
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3 residues can have a contact with metals; S132, H140 and D147.
Between the Cysteine 179 and the Cysteine 214 we can find a disulphide bound which links helix 2 and the helix 3.
The structure shows also an hairpin structure at the N-ter domain.
It exists also a specific loop at R164-S170 residues. This loop aim to stabilize the 129-130 beta-sheet. The R164 is able to make a hydrogen bond with G126, creating a conformational bridge.
A lot of empty structures (not in the secondary structure) are present between helix.
The structure shows moreover a hairpin structure at the N-ter domain.
One of this structure is called 3/10 helix (Each amino acid corresponds to a 120° turn in the helix).
The entire 3haf domain can interact with [http://en.wikipedia.org/wiki/GRB2 Growth factor receptor-bound protein 2] (GRB2), [http://en.wikipedia.org/wiki/Exoribonuclease exoribonuclease 3](ERI3) and [http://en.wikipedia.org/wiki/Synapsin_I Synapsin I] (SYN1).


In the following representation, we can see the alternationof alpha helix and beta sheet, and the different site of interactions:
In the following representation, we can see the alternation of alpha helix and beta sheet, and the different site of interactions:
[[Image:Vjvk.jpg|center|400px||thumb|'''Secondary structure of 3HAF domain''']]
[[Image:Vjvk.jpg|center|400px||thumb|'''Secondary structure of 3HAF domain''']]


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* Ligand
* Quaternary structure
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The protein exists in majority in its dimer form.
Between each helix 144-156 of the two proteins, it exists many interactions whose stabilize the dimer interface. It can be retain acidic and mostly negative residues, or basic and positive residues.
Each helix 171−188 is linked to the C-terminal helix 200−225 of the other monomer. Van der Waals forces are here between such nonpolar residues as valine, isoleucine, and nonpolar sections as histadine, methionine, and glutamic acid.
It occurs hydrogen bonding between the dimers at Thr188 O−Gly195 N, Thr190 O−Lys194 N and Thr192 O−Thr192 N
On each monomer, a hydrogen bond between Asp 202 and Thr 199 stabilize the dimeric structure.
Arg 220 and Ser 132 form a hydrogen bond located at the end of helix 3 which permit the inter-chain interactions to be specific.
The entire 3haf domain can interact with [http://en.wikipedia.org/wiki/GRB2 Growth factor receptor-bound protein 2] (GRB2), [http://en.wikipedia.org/wiki/Exoribonuclease exoribonuclease 3](ERI3) and [http://en.wikipedia.org/wiki/Synapsin_I Synapsin I] (SYN1).
== Ligand and interactions ==
[[Image:Ligand cl.jpg|right|200px||thumb|'''Bond between 3HAF domain and the Ligand Cd2+''']]
[[Image:Ligand cl.jpg|right|200px||thumb|'''Bond between 3HAF domain and the Ligand Cd2+''']]
There are 3 types of '''non-polymeric''' entities that can bind this domain:cadmium ion, chloride ion, water.
There are 3 types of '''non-polymeric''' entities that can bind this domain:cadmium ion, chloride ion, water.


This domain 3HAF of the human prion can bind <scene name='56/568013/Ligand/1'>Ligand</scene>(copper (II) ions) with high affinity: '''Cd2+''' [http://en.wikipedia.org/wiki/Cadmium cadnium ions] and '''Cl-''' (chloride ion). Moreover, the entire protein can bind a Cu2+ ions on this NH2 tail and this bond can induce '''conformational change''' with a lot of unknown effect.
This domain 3HAF of the human prion can bind <scene name='56/568013/Ligand/1'>Ligand</scene>(copper (II) ions) with high affinity: '''Cd2+''' [http://en.wikipedia.org/wiki/Cadmium cadnium ions] and '''Cl-''' (chloride ion). Moreover, the entire protein can bind a Cu2+ ions on this NH2 tail and this bond can induce '''conformational change''' with a lot of unknown effect. 3 others residues can have a contact with metals; S132, H140 and D147.
In fact, the 3haf domain is only one chain with 2 binding sites for residues CD (H40 and D147)and 1 binding domains for CL S132.
In fact, the 3haf domain is only one chain with 2 binding sites for residues CD (H40 and D147)and 1 binding domains for CL S132.


 
The entire 3HAF domain can interact with Growth factor receptor-bound protein 2 (GRB2), exoribonuclease 3(ERI3) and Synapsin I (SYN1). There are 3 types of non-polymeric entities that can bind this domain:cadmium ion, chloride ion, water.
 
For this domain, two glycosylated sites exist on helix 2 and 3 at Asn181 and Asn197.
 




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It’s known that the transformation of the normal protein in its infectious model involves a conversion from a soluble and predominantly α-helical protein to an aggregated form, which is substantially enriched in β-sheet.


The common Methionine/Valine polymorphism residue in 129 in the PrP influences the health because a simple mutation on the valine 129 can have an effect on some disease.
The substitution by a valine at residue 129 influences intermolecular beta-sheet formation and conformation. Even if the structure is not distorted by the substitution (no effect on the stability, folding, or dynamics), the difference is based on the interaction by the beta-sheet between two dimers. With two M129 dimers, there is an identical and stable intermolecular 129-130 beta-sheet interaction. However with two V129 variant dimers, it appears a flexion, form to prevent steric troubles between them. In some cases of variants, the beta-sheet interface is entirely absent. This tendency allows the exposure of beta-sheet to the exterior of the protein and thus occasionally influences the aggregation form and so the development of prions.
If this Valine is muted as methionine (polymorphism) it can determine the disease phenotype in patients. Valine 129 is finding on CJD whereas Methionine 129 is find in FFI.
 
The common Methionine/Valine polymorphism residue in 129 in the PrP influences disease.
For example,valine 129 is finding on CJD whereas methionine 129 is find in FFI.


A lot of others mutations can be finding in these diseases: for example, a substitution of Arginine 208 in  Histidine 208 can hae an effect on mental disease and is finding in CJD. At the same way, a subtitution of Asparagine 171 in Serine 171 can be finding in schizoaffective disorder.
A lot of others mutations can be finding in these diseases: for example, a substitution of Arginine 208 in  Histidine 208 can hae an effect on mental disease and is finding in CJD. At the same way, a subtitution of Asparagine 171 in Serine 171 can be finding in schizoaffective disorder.


For this domain, two glycosylated sites exist on helix 2 and 3 at Asn181 and Asn197. A [http://en.wikipedia.org/wiki/Disulfide_bond disulfide bond] exist between Cys179 (helix 2) and Cys214 (helix 3).
For this 3HAF, two glycosylated sites exist on helix 2 and 3 at Asn181 and Asn197. A [http://en.wikipedia.org/wiki/Disulfide_bond disulfide bond] exist between Cys179 (helix 2) and Cys214 (helix 3).
 
==Biological Application==
PYM


==Function and Regulation==
PYM


==See Also==
==See Also==
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