Prions
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Liverpool group posts contradictory cat sequence
Rohwer group posts cat prion
Lots of UK dogs with TSE -- opinion
Unusual aspects of cat prion -- Alex Bossers
Cat sequences in conflict: alignment
Crocodile prion sequence predicted

Liverpool group posts very different cat sequence

2 Oct 97 GenBank Y13698
Taylor,M.S., Newton,D.J., Flanagan,B.F. and Christmas,S.E.
Department of Immunology, Liverpool, Merseyside, L69 3GA, UK
A 373 bp fragment of cat prion was sequenced by the Liverpool group, corresponding to residues 109-232 in humans or 112-235 in sheep. This is quite sufficient for threading onto mouse and hamster 3D structures. The Liverpool cat sequence shows 8 amino acid differences and 42 nucleotide differences with the Rohwer cat sequence. The sequences show a very low 93% similarity for intra-specific variation so it is impossible that both sequences be correct.

When cat and dog prion amino acid sequences are threaded to refined mouse 3D coordinates, they differ by 0.14 angstroms, rmsd, suggesting that little by way of differential species barrier could exist.

MKHVAGAAAAGAVVGGLGGYMLGSAMSRPLIHFGNDYEDRYYRENMYRYPDQ
VYYRPVDQYSNQNNFVRDCVNITVKQRTVTTTTKGENFTETDMKIMERVEQMCVTQYQKESEAYYQRRASA

>gi|2463040|gnl|PID|e351514 cat prion
MKHVAGAAAAGAVVGGLGGYMLGSAMSRPLIHFGNDYEDRYYRENMYRYPDQVYYRPVDQYSNQNNFVRD
CVNITVKQRTVTTTTKGENFTETDMKIMERVVEQMCVTQYQKESEAYYQRRASA

>gi|2463039|emb|Y13698|FCPRION Felis catus prion  partial, frame 31
ACATGAAGCACGTGGCAGGAGCCGCAGCAGCCGGGGCGGTAGTAGGGGGCCTTGGTGGCTACATGCTGGG
GAGTGCCATGAGCAGGCCACTCATTCATTTTGGCAATGACTATGAGGACCGTTACTATCGTGAGAACATG
TACCGCTACCCCGACCAAGTATACTACCGGCCAGTGGATCAGTACAGCAACCAGAACAACTTTGTGCGTG
ACTGCGTCAACATCACTGTCAAGCAGCGCACAGTGACCACCACCACCAAGGGGGAGAACTTCACAGAGAC
CGACATGAAGATCATGGAGCGTGTGGTGGAGCAGATGTGTGTCACCCAGTACCAGAAGGAGTCCGAGGCT
TACTACCAAAGAAGGGCGAGCGC
  rowher_cat_minimal  MKHVAGAAAA GAVVGGLGGY MLGSAMSRPL IHFGNDYEDR YYRENMYRYP
       liverpool_cat  MKHVAGAAAA GAVVGGLGGY MLGSAMSRPL IHFGNDYEDR YYRENMYRYP
           Consensus  MKHVAGAAAA GAVVGGLGGY MLGSAMSRPL IHFGNDYEDR YYRENMYRYP

                      51                                                 100
  rowher_cat_minimal  NQVYYRPVDQ YSNQNNFVHD CVNITVKQHT VTTTTKGENF TETDIKIMER
       liverpool_cat  DQVYYRPVDQ YSNQNNFVRD CVNITVKQRT VTTTTKGENF TETDMKIMER
           Consensus  #QVYYRPVDQ YSNQNNFVrD CVNITVKQrT VTTTTKGENF TETDiKIMER

                      101                    124
  rowher_cat_minimal  VVEQMCITQY QRESEAYYQR GASV
       liverpool_cat  VVEQMCVTQY QKESEAYYQR RASA
           Consensus  VVEQMC!TQY QrESEAYYQR rASa

Rohwer group posts cat prion

23 Sept 1997   Webmaster
The cat prion sequence was posted on Sept 22, 1997. My earlier prediction had it right for 205 of the first 206 residues considered. However, at residue alternatives the sequence leaned more towards hooved animals. The other 3 changes were conservative, distal, and previously observed: ile for val, arg for lys, and val for ala.

Still, there were unusual features. In a nutshell, cats looked less like mink-ferret and dog-wolf-dingo and more like horse-zebra, and thus inevitably, more like cow-sheep. This is not be itself impoossible for molecular data in the ferungulates. In the 193 aa aligned, cat scored 97% with bovine and 99% with ovine, 94% to ancestral placental mammal. No bizarre destabilizing mutations occur like those found in White Leghorns and sheep -- cats aren't all that domesticated is the bottom line.

>rowher_cat
MVKSHIGSWILVLFVAMWSDVGLCKKRPKPGGGWNTGGSRYPGQ
GSPGGNRYPPQGGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQPHGGGGWGQGGSHSQW
NKPSKPKTNMKHVAGAAAAGAVVGGLGGYMLGSAMSRPLIHFGNDYEDRYYRENMYRY
PNQVYYRPVDQYSNQNNFVHDCVNITVKQHTVTTTTKGENFTETDIKIMERVVEQMCI
TQYQRESEAYYQRGASVILFSSPPVILLISFLIFLIVG

>gi|2406625|gb|AF003087| Felis catus prion, complete cds
ATGGTGAAAAGCCACATAGGCAGCTGGATCCTAGTTCTCTTTGTGGCCATGTGGAGTGACGTTGGCCTCT
GCAAGAAGCGACCAAAACCTGGAGGAGGATGGAACACTGGGGGGAGCCGATACCCGGGACAGGGAAGTCC
TGGAGGCAACCGCTATCCACCTCAGGGAGGGGGTGGCTGGGGTCAGCCCCATGGAGGTGGCTGGGGCCAA
CCTCATGGAGGTGGCTGGGGTCAGCCCCATGGTGGTGGCTGGGGACAGCCACATGGTGGTGGAGGCTGGG
GTCAAGGTGGTAGCCACAGTCAGTggaataagcccagtaagccaaaaaccaACATGAAGCATGTGGCAGG
AGCTGCTGCAGCTGGAGCAGTGGTAGGGGGCCTTGGTGGCTACATGCTGGGAAGTGCCATGAGCAGGCCT
CTTATACATTTTGGCAATGACTATGAGGACCGTTACTATCGTGAAAACATGTACCGTTACCCCAACCAAG
TGTACTACAGACCAGTGGATCAGTATAGTAACCAGAACAACTTTGTGCATGACTGTGTCAACATCACAGT
CAAGCAACACACAGTCACCACCACCACCAAGGGGGAGAACTTCACCGAAACTGACATCAAGATAATGGAG
CGAGTGGTGGAGCAAATGTGCATCACCCAGTACCAGAGAGAATCCGAGGCTTATTACCAAAGAGGGGCAA
GTGTgatcctcTTCTCCTCCCCTCCTGTGATCCTCCTCATCTCTTTCCTCATTTTTCTCATAGTAGGATA
GGGGCAACCTTCCTGTTTTCATTAT
The molecular data is consistent with dogs and cats both at high risk from BSE and scrapie. It seems likely that very large numbers of both dogs and cats must have contracted TSE during the epidemic. 79 cats, or was it 79,000, or 790,000? Dogs could well have a slower course for the disease.

Of course, it would be easy and cheap to do 14-3-3 tests on CSF from some of the tens of thousands of older dogs and cats euthanized each month in London alone. Why speculate on how many dogs or cats got it when it is so easy just to measure? A goodly percentage of older dogs especially, would flunk the test, in my estimation.

But if you don't want to know, you don't ask. The tragedy is that later, as estimating the epidemic in humans becomes a big issue, we will wish all possible measures of species barrier breaching had been made, when it was possible to do them. This opportunity, and many others, is slipping away forever, all so that MAFF doesn't have to take a PR hit on companion animals.

Unusual features of cat sequence

Alex Bossers ... Dutch researcher
Nice work that the cat sequence is posted! Good work and an applause for Rohwers group for posting the sequence immediately! My seq-alerting system gave me a good start this morning.

What 'bothers' me about the cat PrP sequence is that it only differs in 1 amino acid from wildtype-sheep (position 226, E for cat and Q for sheep) and 1 octarepeat plus 7 amino acids from bovine. This would make the hypothesis of BSE passing on to cats less obvious and would suggest that scrapie passing to cats would be more in the picture (based on primary aa comparisons).

Another point that bothers me is that the monoclonal antibody 3F4 reacts with feline prion in immunohistochemistry. The 3F4 monoclonal react very specifically to a region (aa 109-112 of the hamster PrP sequence) containing methionines at aa 109 and 112.

All species so far have these specific methionines (human, hamster, mouse 109M). The cat sequence (3F4+) however does react to 3F4 and one would expect it to have the two metionines also but it doesn't. This would mean that different allelic variants of cat PrP could be present (differing at position 112 V instead of M (hamster numbering) or 115 (cat numbering) and that the sequenced cat allele would be the most uncommen one!??

Comparison or Relevent Sequences

The attached comparisons show that the Rohwer cat comes out with the sheep and the Liverpool cat comes out with the dogs, the Liverpool cat corresponding to residues 109-232 in humans or 112-235 in sheep. (In the tree, the Rohwer sequence is artificially remote from sheep simply because the Q226E change by happens to be the alternative in ferungulates and so is weighted.)

Liverpool cat has two codons that might consistently distinguish felids from canids, H190R and G232R in sheep numbering. Right now, with one species, they are just 'singlets' of no special significance.

The implication is, if cats got BSE, then dogs probably did too, the sequences being so close, using the Liverpool sequence. The Liverpool cat sequence shows 8 amino acid differences and 42 nucleotide differences with the Rohwer cat sequence -- not possible. cat_lpool
MKHVAGAAAAGAVVGGLGGYMLGSAMSRPLIHFGNDYED
RYYRENMYRYPDQVYYR PVDQYSNQNNFVRDCVNITVKQR
TVTTTTKGENFTETDMKIMERVVEQMCVTQYQKESEAYYQRRAS

The mammal-amniote divergence: crocodile prion sequence

Webmaster 9.24.97
Here's the crocodile prion sequence. I would estimate the accuracy to be 99% based on earlier experiences. The method used for weighting sequence characters, low pass fourier filtering in the frequency domain, has been used (unevenly and unknowingly) in phylogeny since the time of Darwin, though no one seems to have realized quite what the rationale for it was.

>best_croc_dna
AAGAAGGGCAAAGGCAAACCCAGTGGTGGGGGCTGGGGCACCGGGAGCCATCGCCAGCCCAGCTACCCCCGCCAGCCGGGCTACCCCCATAATCCACGGTACCCCCACAACCCAGGGTATCCCCATAACCCCGGGTACCCCCACAACCCAGGCTACCCCCACAACCCCGGCTACCCCCAGAACCCTGGCTGGGGTCAGGGCTACAACCCATCCAGCGGAGGAAGCTACCACAACCAAAAGCCATGGAAACCCCCCAAATCCAAGACCAACTTCAAGCACGTGGCGGGGGCAGCAGCGGCGGGTGCCGTGGTGGGGGGCTTGGGGGGCTACGCCATGGGGCGCGTCATGTCAGGGATGCACTACCACTTCGACAGCCCCGACGAGTACCGATGGTGGAACGAGAACTCGGCGCGTTATCCCAACCGGGTTTACTACCGGGATTACAGCAGCCCCGTGCCACAGGACGTGTTCGTGGCCGACTGCTTTAACATCACAGTGACTGAGTACAACATTGGCCCCGCTGCCAAGAAGAACACCTCGGAGGCTGGGCCGGCAGCAAACCAAACGGAGATGGAGATGGAGACCAAGGTGGTGACGAAGGTGATCCGCGAGATGTGCGTGCAGCAGTACCGCGAGTACCGCCTGG

>earlier_cat_prediction
KKRPKPGGGWNTGGSRYPGQGSPGGN 
RYPPQGGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQPHGGGGWGQGG-SH
GQWNKPSKPKTNMKHVAGAAAAGAVVGGLGGYMLGSAMSRPLIHFGNDYE
DRYYRENMYRYPNQVYYRPVDQYSNQNNFVHDCVNITVKQHTVTTTTKGE
NFTETDIKIMERVVEQMCITQYQRESEAYYQRGASVILFSPPP

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