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3HAF Domain
3HAF Domain


Contents

3HAF DOMAIN OF HUMAN PRION: Overview

3HAF Domain-Dimer
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 Creutzfeldt-Jakob Disease(CJD), Fatal Familial Insomnia(FFI) and 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 amyloid plaques in the brain.

3HAF is a variant domain of the 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.


Structure of 3HAF domain
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 (7 helices, 62 residues) and 2% of (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).


PDB ID 3haf

Drag the structure with the mouse to rotate
3haf, resolution 2.26Å ()
Ligands: ,
Gene: PRNP, PRIP, PRP (Homo sapiens)
Related: 3hak
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml




Tertiary structure

Between the Cysteine 179 and the Cysteine 214 we can find a 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 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 of the other one. 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 , Thr190 O−Lys194 N and Thr192 O−Thr192 N. On each monomer, a hydrogen bond between stabilizes the dimeric structure. form a hydrogen bond located at the end of helix 3 which permit inter-chain interactions to be specific.


Ligands and Interactions

Bond between 3HAF domain and the Ligand Cl-
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 (copper (II) ions) with high affinity: 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 Growth factor receptor-bound protein 2 (GRB2), exoribonuclease 3(ERI3) and Synapsin I (SYN1). For this domain, two glycosylated sites exist on helix 2 and 3 at Asn181 and Asn197.



Repercussion of the M129/V129 polymorphism

Polymorphism of beta sheet interface
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 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

References

  • Lee S, Antony L, Hartmann R, Knaus KJ, Surewicz K, Surewicz WK, Yee VC. Conformational diversity in prion protein variants influences intermolecular beta-sheet formation. EMBO J. 2010 Jan 6;29(1):251-62. Epub 2009 Nov 19. PMID:19927125 doi:10.1038/emboj.2009.333



Protreopedia Page Contributors and Editors

Pierre-Yves MOCAER and Laurane LEXCELLENT

Student 1A ESBS (Promo 2016)

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