Prion Picture Gallery
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Prion Picture Gallery

Reverse chron order. Last update: 12 Dec 97. Images by webmaster (except as noted).
The image directory below provide access to a fantastic image gallery of the prion protein molecule, including normal wild type protein in various species, various mutant forms that cause CJD, and various alleles modulating susceptibility to TSEs including scrapie alleles of sheep. Pathology slides of CJD, kuru, BSE, and scrapie are shown elsewhere.

You may view these images in a choice of formats :

  • as simple flat 2D labelled gif or jpeg images, usually as a series of increasing blow-ups,
  • as a dynamic interactive 3D image within the browser (get plugins and viewers),
  • as a raw xyz coordinate pdb file useful in viewer freeware.

    Clicking on a 3D image will bounce you to the viewer download page if you do not have the browser plugins Chime, Kinemage, or equivalent installed. Don't miss out by failing to install this amazing 3D interactive viewing software. Two itty-bitty tricks are needed to make your own high quality 2D images from these.

    fibril.gif
    fibril persp.gif
    4x fiber.gif

    anti-parallel.pdb
    AP sheet.gif
    parallel.pdb.

    solid fibril.3dmf
    hollow fibril.3dmf
    A universal cross-beta structure describes the congophilic fiber of amyloid diseases, including prion disease, as noted by GG Glenner in 1980, NEJM 302:1283;1333. Chou and Martin determined the dimensions of prion fibrils in 1971. The amyloid fiber is a coil of several fibrils, themselves helical beta sheet of strands perpendicular to a cylindrical axis. The repeat unit is 115 angstroms; a peptide strand occupies 4.8A; so 24 strands per repeat with rotation of 360/24=15 degrees and right-hand twist [Chothia 1973]. The gifs show 12 fibrils (groupable as 1, 2, 3, 4, or 6) wrapping with a hollow (resp. solid) tube of ratio 44:100 and a non-supercoiled fiber comprised of 4 fibrils (roughly , transthyretin). Perhaps 3-4 consecutive strands on a sheet are grouped as prion monomer, the next 3-4 as a second monomer oriented so the junction is anti-parallel (and binds Congo Red).Interactive parallel and anti-parallel beta sheets from PDB show hydrogen bonding and side-chain positioning. More difficult virtual reality files enable you to fly-throughs of the prion fibril.
    core.gif
    thr 191.gif
    asp 202.gif
    ser 222.gif
    Going by the 6,000 entries at the protein data base, polar and charged residues can be buried in the interior of a protein only when they are fully hydrogen bonded. Thr 183 and Ser 222 are the most extreme polar residues in mouse prion with only 5% solvent exposure. Asn 153, gln 172, asn 174, his 187, thr 191, and asp 202 come next, with 10% exposure. Hydrogen-bonding partners are not given consistently in mouse and hamster structures at current levels of refinement.

    The extreme hydrophobic core consists of tyr 150, phe 175, cys 179, met 206, val 209, val 210, met 213, cys 214, and val 215, with1% available to solvent. The most exposed residues are lys 220, lys 194, his 140, glu 200, gln 223, and asp 167 at 50% or more.

    epitope.gif
    dimer.gif

    3d dimer1.pdb
    3d dimer2 .pdb
    The first image summarizes epitope locations from Oesch et al, a study from Prusiner's group, and a recent PNAS paper on 'protein x' interacting residues. The second image shows a prion dimer that brings epitopes 1 adjacent to 2 and 3 while burying tyrosines; pdb coordinates are also provided for the 'sickle-cell' and a trp 145/tyr169 dimers. It is getting increasingly difficult to summarize in a single image all sites and regions on the prion molecule even with no molecular visualization yet of the two bulky carbohydrate substituents.
    mutations.gif
    conformers.gif
    epitopeX.gif

    N171S pdb
    The first image shows a compilation of known human mutations displayed on mouse, including the new N171S. The second shows alpha helix in beta sheet in the normal and rogue conformer [speculative]. The third shows a proposed binding site for protein X and hypothetical rogue prion in beta sheet conformatioon. Gln168, Gln172, Thr215, and Gln219 form part of the site of protein X binding. These side chains are on the surface of helix 3, forming a discontinuous epitope with residues 167 and 171 in an adjacent loop. Substitutions of basic residues at 167, 171, 214, or 218 prevent rogue prion formation, acting as dominant negatives by sequestering protein X. PNAS
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    flat 5*

    3D h ..Kin h
    3D m..Kin m
    3D mb
    These images show hamster and mouse prion proteins. The mouse structure is refined but shorter in length than the hamster. Some problems remain. The beautiful superpositioning of the two proteins is due to Roland Riek; the set of hamster is from James et al. article in PNAS. Hamster maintains a striking positive face first observed in mouse. Met 129, a modulating locus in humans, is seen to bind tightly with Tyr 163 in the VYYR -YMLG beta sheet.
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    The long incubation strain of mouse whose structure was determined differs from short incubation mouse (surprisingly, wild type) at two amino acids, M109F and T189V . The odd M109F substitution results in hudrophobic phenylalanine inappropriately on the exterior of the molecule in place of threonine, threading from hamster. The T189V substitution in helix 3 of long incubation mouse is again a hydrophobic residue, valine, inappropriately on the exterior of the molecule inplace of a polar residue.
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    3D a
    3D b
    3D c
    E200K is a common human mutation causing CJD. The context is NFTE, the second glycosylation site. F198S is another CJD-causing mutation in this region. The 200 codon is glutamate with no exceptions in vertebrates. It occurs just before helix 3. The graphics show where the glutamate to lysine substitution occurs, then compare geometry in this region between mouse and hamster nmr structures. The only real neighbor is Lys 204; Arg 208 is nearby. The hamster shows important differences to mouse, most notably that E200 and K204 are touching in the van der Waal sense and seem to be hydrogen bonding. The 3D models suggested a mechanism of destabilization: E200K brings two positively charged lysines together.
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    3D
    That A117V causes CJD is no surprise, as AGAAAAGAVVGGLGG by far the most strongly conserved during evolution. What's so special about this particular alanine? Ala 117 hydrogen bonds to 3 other residues: Gly 119, Val 121, and Leu 130. Its side chain extends into the solvent, but a valine cannot do this easily; it would want to be buried, disrupting the hydrogen bond network. Met 129 is here too. A valine at 117 would change domain docking and everything subsequent. Other hydrogen bonds occur in this cluster as well, V161-G131, G123-A120, and Tyr 163-M129).
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    3D
    Fatal familial insomnia, D178N, context DCVNIT, may result from blocked export due to missing glycosylation or disulphide formation. There is no steric significance to changing a aspartic acid to a asparagine. Neighboring Arg 164 don't seem to interact with Glu178 though its charge could offset arginine. D178N, V180I, and T183A are a cluster having similar structural effects, though phenotypes differ. In V180I, valine and isoleucine are so similar in shape and properties, some subtle interior hydrophobic packing issue, missing rotamers must arise. The valine occupies a delicate site, sandwiched between a disulphide cysteine and a glycosylation recognition site. T183A is the new Brazilian mutant that has lost its first glycosylation site.
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    3D
    Q217R suggests change in charge type matters at this location; the context is QYE, where the glutamate is a neutral modulating polymorphism. Curiously, Q217R is in the same 3D pocket as the disulphide (4.6 A) and the FFI region DCVNIT (8.2 A), this couldn't be guessed from the sequence. It seems to be forming a hydrogen bonding chain, Gln217- Arg164 (4.0 A)-Cys 214 (carbonyl) not including Asn 178. These bonds are very strongly supported in hamster. Residues that interact in a dimer interface (or in a heterodimer) can't be understood from just considering a monomer.
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    3D shmou
    3D shham
    These images show the environment of the allele L141F in sheep relative to the hamster and mouse structures. This allele is less worrisome than some others because L141M, L141I, and L141V are seen in other species. The region overall has seen rapid change and is not alignable with avian sequences. Note the marked shift in codon 141 in hamster relative to mouse, even though the hydrogen bond between Arg 154 and Asp 150 is found in both: this is consistent with non-criticality of this domain.
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    3D shmou
    3D shham
    These images show the environment of the allele A136V in sheep relative to the hamster and mouse structures. These changes are unfortunately located: shortly after the first beta strand (which has been a fixture for 310 million years +). Here we find two fairly conservative substitutions but in a region that has never tolerated any subsitution (32/38 consecutive residues invariant back to the amniote divergence): YMLG S A M SRP invariant placental mammal.

    Trick one: cut the coordinate text file, say 1AG2 for mouse, down in a text editor to just the residues you want to display, not worrying about missing connectors. Point your browser at the pdb as a Chime file. Tweak the model with the pop-up menus until it's how you want it. Then set the monitor to maximum screen size, screen res, and color bit depth, ie 17", 1600x1200, millions. Resize the model to fit, turn on rendering.

    Trick two: take a screen shot. Get the monitor back to normal, put on text and arrows and tweak colors, set aside an RGB copy for printing and non-lossy editing, dumb the image down in Photoshop with bicubic convolution to desired final size and screen res, save as high quality jpeg for Web.

    Not exactly rocket science: five minutes from concept to final 'published' product -- this is the 90's, get used to it. But be wary of underlying accuracy and meaningfuness of the data ... there is still such a thing as garbage in, stunning garbage out. -- webmaster.

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