Proteopedia - User contributions [en]

Sandbox Reserved 815

2014-01-09T19:49:15Z

Pierre-Yves Mocaer:

{{Sandbox-reserved-ESBS}}


[[Image:54.jpg|right|550px|thumb|'''3HAF Domain''']]

=3HAF DOMAIN OF HUMAN PRION: Overview=
[[Image:3haf bio r 500.jpg|left|220px|thumb|'''3HAF Domain-Dimer''']]

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 [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].

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 misfolded proteins induces the death of cells and the accumulation of [http://en.wikipedia.org/wiki/Amyloid amyloid plaques] in the brain.

3HAF is a variant domain of the [http://www.proteopedia.org/wiki/index.php/Human_Prion_Protein_Dimer major protein prion] going from residue 90 to 231. Compare to the sequence of the major prion protein, a Valine substitutes a Methionine at the 129 residue, which influence the susceptibility of the formation of the prion.

=Structure=

The 3HAF structure results from a work leaded by Lee S. in 2010, in which the team has characterized seven variants of the human prion. The structure was determined by XRAY diffraction in a 2.26-Angstrom resolution.

[[Image:Vjvk.jpg|left|350px||thumb|'''Structure of 3HAF domain''']]

==Secondary Structure==

The unique chain of 3HAF is constituted of 7 helices (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-sheets (129-130 and 160-163).
The proportion of each structure is 43% of <scene name='56/568013/Alpha_helix/9'>Alpha Helix</scene>(7 helices, 62 residues) and 2% of <scene name='56/568013/Beta_sheet/1'>Beta Sheet</scene> (2 strands, 4 residues).

A lot of empty structures are present between helices.
One of the structure is called 3/10 helix (Each amino acid corresponds to a 120° turn in the helix).

{{STRUCTURE_3haf| PDB=3haf | SCENE= }}

==Tertiary structure==

Between the Cysteine 179 and the Cysteine 214 we can find a <scene name='56/568013/B/1'>disulphide bond</scene> which links helix 2 and the helix 3.
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.
The structure shows moreover a hairpin structure at the N-ter domain.

==Quaternary structure==

The protein exists in majority in its dimer form.
Between each <scene name='User:Erin_May/Sandbox_1/Nonpolar_at_dimer_interface/2'> helix 144-156</scene> 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 monomere is linked to the C-terminal <scene name='User:Erin_May/Sandbox_1/Helix_2_with_helix_3/1'> helix 200-225</scene> of the other one. [http://en.wikipedia.org/wiki/Van_der_Waals_forces 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 bonds between the dimers at <scene name='User:Erin_May/Sandbox_1/Interface_hydrogen_bonding/1'> Thr188 O Gly195 N</scene>, Thr190 O−Lys194 N and Thr192 O−Thr192 N.
On each monomer, a hydrogen bond between <scene name='User:Erin_May/Sandbox_1/Hydrogen_bond_asp_202/1'> Asp 202 and Thr 199</scene> stabilizes the dimeric structure.
<scene name='User:Erin_May/Sandbox_1/Hydrogen_bonding/1'> Arg 220 and Ser 132</scene> form a hydrogen bond located at the end of helix 3 which permit inter-chain interactions to be specific.

=Ligands and Interactions =

[[Image:Ligand cl.jpg|left|200px||thumb|'''Bond between 3HAF domain and the Ligand Cl-''']]

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: [http://en.wikipedia.org/wiki/Cadmium '''Cd2+'''] and '''Cl-''' . Moreover, the entire protein can bind a Cu2+ ion on this NH2 tail and this bond can induce '''conformational changes''' with a lot of unknown effects. 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.

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).
For this domain, two [http://en.wikipedia.org/wiki/Glycosylation glycosylated sites] exist on helix 2 and 3 at Asn181 and Asn197.

=Repercussion of the M129/V129 polymorphism =

[[Image:Yes.jpg|left|500px||thumb|'''Polymorphism of beta sheet interface''']]

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

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 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808380/figure/f3/ the exposure of beta-sheet to the exterior of the protein] and thus occasionally '''influences the aggregation form''' and so the development of prions.

The common Methionine/Valine polymorphism residue in 129 in the prion protein influences disease.
For example, Valine 129 is finding on CJD whereas methionine 129 is finding in FFI.

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

=See Also=
*[[Prion|Prion]]
*[http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=3haf&template=main.html PDBSum]
*[http://www.ebi.ac.uk/pdbe-srv/view/entry/3haf/summary.html EMBISum]
*[http://proteopedia.org/wiki/index.php/3haf Proteopedia prion]
*[http://www.rcsb.org/pdb/explore.do?structureId=3HAF EBISum]

=References=
<ref group="xtra">PMID:019927125</ref><references group="xtra"/><references/>
<ref group="xtra">PMID:17661791</ref><references group="xtra"/><references/>

[[Category: Homo sapiens]]
[[Category: Antony, L.]]
[[Category: Hartmann, R.]]
[[Category: Knaus, K J.]]
[[Category: Lee, S.]]
[[Category: Surewicz, K.]]
[[Category: Surewicz, W K.]]
[[Category: Yee, V C.]]
[[Category: Cell membrane]]
[[Category: Disease mutation]]
[[Category: Disulfide bond]]
[[Category: Glycoprotein]]
[[Category: Golgi apparatus]]
[[Category: Gpi-anchor]]
[[Category: Lipoprotein]]
[[Category: Membrane]]
[[Category: Membrane protein]]
[[Category: Prion]]

=Protreopedia Page Contributors and Editors=

Pierre-Yves MOCAER and Laurane LEXCELLENT

Student 1A ESBS (Promo 2016)

2014-01-09T16:35:52Z

Pierre-Yves Mocaer:

Sandbox Reserved 815

2014-01-09T16:35:27Z

Pierre-Yves Mocaer:

Sandbox Reserved 815

2014-01-09T16:34:40Z

Pierre-Yves Mocaer:

2014-01-09T16:21:49Z

Pierre-Yves Mocaer:

{{Sandbox-reserved-ESBS}}


[[Image:54.jpg|right|550px|thumb|'''3HAF Domain''']]

3HAf domain

=Introduction=
[[Image:3haf bio r 500.jpg|left|220px|thumb|'''3HAF Domain-Dimer''']]

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].

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 vaiant domain of the major [http://www.proteopedia.org/wiki/index.php/Human_Prion_Protein_Dimer 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=

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.

[[Image:Vjvk.jpg|left|350px||thumb|'''Structure of 3HAF domain''']]

==Secondary Structure==

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).

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).

{{STRUCTURE_3haf| PDB=3haf | SCENE= }}

==Tertiary structure==

Between the Cysteine 179 and the Cysteine 214 we can find a <scene name='56/568013/B/1'>disulphide bound</scene> which links helix 2 and the helix 3.
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.
The structure shows moreover a hairpin structure at the N-ter domain.

==Quaternary structure==

The protein exists in majority in its dimer form.
Between each <scene name='User:Erin_May/Sandbox_1/Nonpolar_at_dimer_interface/2'> helix 144-156</scene> 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 is linked to the C-terminal <scene name='User:Erin_May/Sandbox_1/Helix_2_with_helix_3/1'> helix 200-225</scene> of the other monomer. [http://en.wikipedia.org/wiki/Van_der_Waals_forces 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 <scene name='User:Erin_May/Sandbox_1/Interface_hydrogen_bonding/1'>Thr188 O−Gly195 N</scene>, Thr190 O−Lys194 N and Thr192 O−Thr192 N
On each monomer, a Hydrogen bond between <scene name='User:Erin_May/Sandbox_1/Hydrogen_bond_asp_202/1'> Asp 202 and Thr 199</scene> stabilize the dimeric structure.
<scene name='User:Erin_May/Sandbox_1/Hydrogen_bonding/1'> Arg 220 and Ser 132</scene> form a Hydrogen bond located at the end of helix 3 which permit the inter-chain interactions to be specific.

= Ligand and interactions =

[[Image:Ligand cl.jpg|left|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.

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.

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). 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.

= Repercussion of the M129/V129 polymorphism =

[[Image:C:\Users\Pierre-Yves\Desktop\images.jpg]]

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 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 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808380/figure/f3/ the exposure of beta-sheet to the exterior of the protein] and thus occasionally influences the aggregation form and so the development of prions.

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.

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).

=See Also=
*[[Prion|Prion]]
*[http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=3haf&template=main.html PDBSum]
*[http://www.ebi.ac.uk/pdbe-srv/view/entry/3haf/summary.html EMBISum]

=Reference=
<ref group="xtra">PMID:019927125</ref><references group="xtra"/><references/>
[[Category: Homo sapiens]]
[[Category: Antony, L.]]
[[Category: Hartmann, R.]]
[[Category: Knaus, K J.]]
[[Category: Lee, S.]]
[[Category: Surewicz, K.]]
[[Category: Surewicz, W K.]]
[[Category: Yee, V C.]]
[[Category: Cell membrane]]
[[Category: Disease mutation]]
[[Category: Disulfide bond]]
[[Category: Glycoprotein]]
[[Category: Golgi apparatus]]
[[Category: Gpi-anchor]]
[[Category: Lipoprotein]]
[[Category: Membrane]]
[[Category: Membrane protein]]
[[Category: Prion]]