Prion protein contains three alpha-helical stretches, according to the 3D-NMR structural fragment described in the 11 July 1996 Nature. The first helix was anomalous in not being amphipathic: normally, looking down the axis of an alpha helix in the 'helical wheel' projection, one sees polar surface residues on one side and hydrophobic interior residues on the other. Amphipathic refers to these two faces. The problem with helix H1 can be seen clearly from a graph of Kyte-Doolittle hydrophobicity values or the wheel below.
Wuthrich linked this observation to a proposal that the four-residue beta sheet could nucleate a much more extensive beta sheet that could be induced to propagate through this weakly bound alpha helix and loop, yielding a conformational shift to the long-sought scrapie form of prion protein. The scrapie form might then be protease-resistant because vulnerable loop regions are now protected.
Click here to see an animation of this hypothetical process.
Space coordinates for the helical structures are unpublished. In an ideal alpha helix, there are 3.6 residues per complete rotation so a rotation of 100 degrees per residue, in the clockwise direction looking N-terminal to C. Since 18 amino acids give 5 complete turns, positions of side chains begin superimposing in projection with this periodicity. Mouse prion has helices of length 11, 15, and 18, as shown in the table below. Note that helix 3 has a bent non-ideal axis; perhaps relaxation of axial strain favors the rogue conformer. A graphic of helical-forming tendency is also provided below [values from O'Neil and DeGrado, Science 250:646 1990]; proline is seen to be totally disruptive for the N-terminal invariant core.
In addition to helical wheels for mouse prion, it is useful to align helices from the 34 species where the prion sequence is known and compute average Kyte-Doolittle hydrophobic values [or similar measures] to visualize conserved features in the composite wheel. Amino acids are strongly conserved overall in the helical and beta strand regions, so this results in minimal change from conclusions drawn for the mouse (except for chicken).
Helices of mouse prion protein
Residues in magenta change in familial CJD, as shown in blue.
Residues said to be in the hydrophobic core are underlined.
The two cysteines form a disulphide bond.
helix # position CJD helical amino acids turns 3 letter code H1 11 144-154 Y DWEDR YYREN M 3.06 asp trp glu asp arg tyr tyr arg glu asn met H2 15 179-193 I CVNIT IKQHT VTTTT 4.17 cys val asn ile thr ile lys gln his thr val thr thr thr thr H3 18 200-217 KIR ETDVK MMERV VEQMC VTQ 5.00 glu thr asp val lys met met glu arg val val glu gln met cys val thr gln
of amino acids along
four regions of prion protein.
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