U.S. patent application number 16/940080 was filed with the patent office on 2020-11-12 for rna-guided targeting of genetic and epigenomic regulatory proteins to specific genomic loci. The applicant listed for this patent is The General Hospital Corporation. Invention is credited to J. Keith Joung, Morgan Maeder.
Application Number | 20200354704 16/940080 |
Document ID | / |
Family ID | 1000004975387 |
Filed Date | 2020-11-12 |
United States Patent Application | 20200354704 |
Kind Code | A1 |
Joung; J. Keith ; et al. | November 12, 2020 |
Methods and constructs for RNA-guided targeting of transcriptional activators to specific genomic loci.
Inventors: | Joung; J. Keith; (Winchester, MA) ; Maeder; Morgan; (Brookline, MA) | ||||||||||
Applicant: |
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Family ID: | 1000004975387 | ||||||||||
Appl. No.: | 16/940080 | ||||||||||
Filed: | July 27, 2020 |
Application Number | Filing Date | Patent Number | ||
---|---|---|---|---|
14211117 | Mar 14, 2014 | 10760064 | ||
16940080 | ||||
61799647 | Mar 15, 2013 | |||
Current U.S. Class: | 1/1 |
Current CPC Class: | C07K 2319/43 20130101; C12N 9/22 20130101; C12N 2310/3341 20130101; C12N 2310/318 20130101; C07K 2319/40 20130101; C12N 2310/20 20170501; C07K 14/4705 20130101; C12N 15/1136 20130101; C12N 15/63 20130101; C12N 2310/3231 20130101; C07K 2319/80 20130101 |
International Class: | C12N 9/22 20060101 C12N009/22; C07K 14/47 20060101 C07K014/47; C12N 15/63 20060101 C12N015/63; C12N 15/113 20060101 C12N015/113 |
Sequence CWU 1
1
718PRTArtificial Sequencenuclear localization signal 1Pro Lys Lys
Lys Arg Lys Val Ser1 5250PRTArtificial SequenceVP64 transcriptional
activator sequence 2Asp Ala Leu Asp Asp Phe Asp Leu Asp Met Leu Gly
Ser Asp Ala Leu1 5 10 15Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp
Ala Leu Asp Asp Phe 20 25 30Asp Leu Asp Met Leu Gly Ser Asp Ala Leu
Asp Asp Phe Asp Leu Asp 35 40 45Met Leu 5031368PRTArtificial
Sequencecatalytically inactive Cas9 3Met Asp Lys Lys Tyr Ser Ile
Gly Leu Ala Ile Gly Thr Asn Ser Val1 5 10 15Gly Trp Ala Val Ile Thr
Asp Glu Tyr Lys Val Pro Ser Lys Lys Phe 20 25 30Lys Val Leu Gly Asn
Thr Asp Arg His Ser Ile Lys Lys Asn Leu Ile 35 40 45Gly Ala Leu Leu
Phe Asp Ser Gly Glu Thr Ala Glu Ala Thr Arg Leu 50 55 60Lys Arg Thr
Ala Arg Arg Arg Tyr Thr Arg Arg Lys Asn Arg Ile Cys65 70 75 80Tyr
Leu Gln Glu Ile Phe Ser Asn Glu Met Ala Lys Val Asp Asp Ser 85 90
95Phe Phe His Arg Leu Glu Glu Ser Phe Leu Val Glu Glu Asp Lys Lys
100 105 110His Glu Arg His Pro Ile Phe Gly Asn Ile Val Asp Glu Val
Ala Tyr 115 120 125His Glu Lys Tyr Pro Thr Ile Tyr His Leu Arg Lys
Lys Leu Val Asp 130 135 140Ser Thr Asp Lys Ala Asp Leu Arg Leu Ile
Tyr Leu Ala Leu Ala His145 150 155 160Met Ile Lys Phe Arg Gly His
Phe Leu Ile Glu Gly Asp Leu Asn Pro 165 170 175Asp Asn Ser Asp Val
Asp Lys Leu Phe Ile Gln Leu Val Gln Thr Tyr 180 185 190Asn Gln Leu
Phe Glu Glu Asn Pro Ile Asn Ala Ser Gly Val Asp Ala 195 200 205Lys
Ala Ile Leu Ser Ala Arg Leu Ser Lys Ser Arg Arg Leu Glu Asn 210 215
220Leu Ile Ala Gln Leu Pro Gly Glu Lys Lys Asn Gly Leu Phe Gly
Asn225 230 235 240Leu Ile Ala Leu Ser Leu Gly Leu Thr Pro Asn Phe
Lys Ser Asn Phe 245 250 255Asp Leu Ala Glu Asp Ala Lys Leu Gln Leu
Ser Lys Asp Thr Tyr Asp 260 265 270Asp Asp Leu Asp Asn Leu Leu Ala
Gln Ile Gly Asp Gln Tyr Ala Asp 275 280 285Leu Phe Leu Ala Ala Lys
Asn Leu Ser Asp Ala Ile Leu Leu Ser Asp 290 295 300Ile Leu Arg Val
Asn Thr Glu Ile Thr Lys Ala Pro Leu Ser Ala Ser305 310 315 320Met
Ile Lys Arg Tyr Asp Glu His His Gln Asp Leu Thr Leu Leu Lys 325 330
335Ala Leu Val Arg Gln Gln Leu Pro Glu Lys Tyr Lys Glu Ile Phe Phe
340 345 350Asp Gln Ser Lys Asn Gly Tyr Ala Gly Tyr Ile Asp Gly Gly
Ala Ser 355 360 365Gln Glu Glu Phe Tyr Lys Phe Ile Lys Pro Ile Leu
Glu Lys Met Asp 370 375 380Gly Thr Glu Glu Leu Leu Val Lys Leu Asn
Arg Glu Asp Leu Leu Arg385 390 395 400Lys Gln Arg Thr Phe Asp Asn
Gly Ser Ile Pro His Gln Ile His Leu 405 410 415Gly Glu Leu His Ala
Ile Leu Arg Arg Gln Glu Asp Phe Tyr Pro Phe 420 425 430Leu Lys Asp
Asn Arg Glu Lys Ile Glu Lys Ile Leu Thr Phe Arg Ile 435 440 445Pro
Tyr Tyr Val Gly Pro Leu Ala Arg Gly Asn Ser Arg Phe Ala Trp 450 455
460Met Thr Arg Lys Ser Glu Glu Thr Ile Thr Pro Trp Asn Phe Glu
Glu465 470 475 480Val Val Asp Lys Gly Ala Ser Ala Gln Ser Phe Ile
Glu Arg Met Thr 485 490 495Asn Phe Asp Lys Asn Leu Pro Asn Glu Lys
Val Leu Pro Lys His Ser 500 505 510Leu Leu Tyr Glu Tyr Phe Thr Val
Tyr Asn Glu Leu Thr Lys Val Lys 515 520 525Tyr Val Thr Glu Gly Met
Arg Lys Pro Ala Phe Leu Ser Gly Glu Gln 530 535 540Lys Lys Ala Ile
Val Asp Leu Leu Phe Lys Thr Asn Arg Lys Val Thr545 550 555 560Val
Lys Gln Leu Lys Glu Asp Tyr Phe Lys Lys Ile Glu Cys Phe Asp 565 570
575Ser Val Glu Ile Ser Gly Val Glu Asp Arg Phe Asn Ala Ser Leu Gly
580 585 590Thr Tyr His Asp Leu Leu Lys Ile Ile Lys Asp Lys Asp Phe
Leu Asp 595 600 605Asn Glu Glu Asn Glu Asp Ile Leu Glu Asp Ile Val
Leu Thr Leu Thr 610 615 620Leu Phe Glu Asp Arg Glu Met Ile Glu Glu
Arg Leu Lys Thr Tyr Ala625 630 635 640His Leu Phe Asp Asp Lys Val
Met Lys Gln Leu Lys Arg Arg Arg Tyr 645 650 655Thr Gly Trp Gly Arg
Leu Ser Arg Lys Leu Ile Asn Gly Ile Arg Asp 660 665 670Lys Gln Ser
Gly Lys Thr Ile Leu Asp Phe Leu Lys Ser Asp Gly Phe 675 680 685Ala
Asn Arg Asn Phe Met Gln Leu Ile His Asp Asp Ser Leu Thr Phe 690 695
700Lys Glu Asp Ile Gln Lys Ala Gln Val Ser Gly Gln Gly Asp Ser
Leu705 710 715 720His Glu His Ile Ala Asn Leu Ala Gly Ser Pro Ala
Ile Lys Lys Gly 725 730 735Ile Leu Gln Thr Val Lys Val Val Asp Glu
Leu Val Lys Val Met Gly 740 745 750Arg His Lys Pro Glu Asn Ile Val
Ile Glu Met Ala Arg Glu Asn Gln 755 760 765Thr Thr Gln Lys Gly Gln
Lys Asn Ser Arg Glu Arg Met Lys Arg Ile 770 775 780Glu Glu Gly Ile
Lys Glu Leu Gly Ser Gln Ile Leu Lys Glu His Pro785 790 795 800Val
Glu Asn Thr Gln Leu Gln Asn Glu Lys Leu Tyr Leu Tyr Tyr Leu 805 810
815Gln Asn Gly Arg Asp Met Tyr Val Asp Gln Glu Leu Asp Ile Asn Arg
820 825 830Leu Ser Asp Tyr Asp Val Asp Ala Ile Val Pro Gln Ser Phe
Leu Lys 835 840 845Asp Asp Ser Ile Asp Asn Lys Val Leu Thr Arg Ser
Asp Lys Asn Arg 850 855 860Gly Lys Ser Asp Asn Val Pro Ser Glu Glu
Val Val Lys Lys Met Lys865 870 875 880Asn Tyr Trp Arg Gln Leu Leu
Asn Ala Lys Leu Ile Thr Gln Arg Lys 885 890 895Phe Asp Asn Leu Thr
Lys Ala Glu Arg Gly Gly Leu Ser Glu Leu Asp 900 905 910Lys Ala Gly
Phe Ile Lys Arg Gln Leu Val Glu Thr Arg Gln Ile Thr 915 920 925Lys
His Val Ala Gln Ile Leu Asp Ser Arg Met Asn Thr Lys Tyr Asp 930 935
940Glu Asn Asp Lys Leu Ile Arg Glu Val Lys Val Ile Thr Leu Lys
Ser945 950 955 960Lys Leu Val Ser Asp Phe Arg Lys Asp Phe Gln Phe
Tyr Lys Val Arg 965 970 975Glu Ile Asn Asn Tyr His His Ala His Asp
Ala Tyr Leu Asn Ala Val 980 985 990Val Gly Thr Ala Leu Ile Lys Lys
Tyr Pro Lys Leu Glu Ser Glu Phe 995 1000 1005Val Tyr Gly Asp Tyr
Lys Val Tyr Asp Val Arg Lys Met Ile Ala Lys 1010 1015 1020Ser Glu
Gln Glu Ile Gly Lys Ala Thr Ala Lys Tyr Phe Phe Tyr Ser1025 1030
1035 1040Asn Ile Met Asn Phe Phe Lys Thr Glu Ile Thr Leu Ala Asn
Gly Glu 1045 1050 1055Ile Arg Lys Arg Pro Leu Ile Glu Thr Asn Gly
Glu Thr Gly Glu Ile 1060 1065 1070Val Trp Asp Lys Gly Arg Asp Phe
Ala Thr Val Arg Lys Val Leu Ser 1075 1080 1085Met Pro Gln Val Asn
Ile Val Lys Lys Thr Glu Val Gln Thr Gly Gly 1090 1095 1100Phe Ser
Lys Glu Ser Ile Leu Pro Lys Arg Asn Ser Asp Lys Leu Ile1105 1110
1115 1120Ala Arg Lys Lys Asp Trp Asp Pro Lys Lys Tyr Gly Gly Phe
Asp Ser 1125 1130 1135Pro Thr Val Ala Tyr Ser Val Leu Val Val Ala
Lys Val Glu Lys Gly 1140 1145 1150Lys Ser Lys Lys Leu Lys Ser Val
Lys Glu Leu Leu Gly Ile Thr Ile 1155 1160 1165Met Glu Arg Ser Ser
Phe Glu Lys Asn Pro Ile Asp Phe Leu Glu Ala 1170 1175 1180Lys Gly
Tyr Lys Glu Val Lys Lys Asp Leu Ile Ile Lys Leu Pro Lys1185 1190
1195 1200Tyr Ser Leu Phe Glu Leu Glu Asn Gly Arg Lys Arg Met Leu
Ala Ser 1205 1210 1215Ala Gly Glu Leu Gln Lys Gly Asn Glu Leu Ala
Leu Pro Ser Lys Tyr 1220 1225 1230Val Asn Phe Leu Tyr Leu Ala Ser
His Tyr Glu Lys Leu Lys Gly Ser 1235 1240 1245Pro Glu Asp Asn Glu
Gln Lys Gln Leu Phe Val Glu Gln His Lys His 1250 1255 1260Tyr Leu
Asp Glu Ile Ile Glu Gln Ile Ser Glu Phe Ser Lys Arg Val1265 1270
1275 1280Ile Leu Ala Asp Ala Asn Leu Asp Lys Val Leu Ser Ala Tyr
Asn Lys 1285 1290 1295His Arg Asp Lys Pro Ile Arg Glu Gln Ala Glu
Asn Ile Ile His Leu 1300 1305 1310Phe Thr Leu Thr Asn Leu Gly Ala
Pro Ala Ala Phe Lys Tyr Phe Asp 1315 1320 1325Thr Thr Ile Asp Arg
Lys Arg Tyr Thr Ser Thr Lys Glu Val Leu Asp 1330 1335 1340Ala Thr
Leu Ile His Gln Ser Ile Thr Gly Leu Tyr Glu Thr Arg Ile1345 1350
1355 1360Asp Leu Ser Gln Leu Gly Gly Asp 136542279DNAArtificial
Sequenceguide RNA expression vector
sequencemisc_feature(331)...(350)n = A, T, C or G 4gacgtcgcta
gctgtacaaa aaagcaggct ttaaaggaac caattcagtc gactggatcc 60ggtaccaagg
tcgggcagga agagggccta tttcccatga ttccttcata tttgcatata
120cgatacaagg ctgttagaga gataattaga attaatttga ctgtaaacac
aaagatatta 180gtacaaaata cgtgacgtag aaagtaataa tttcttgggt
agtttgcagt tttaaaatta 240tgttttaaaa tggactatca tatgcttacc
gtaacttgaa agtatttcga tttcttggct 300ttatatatct tgtggaaagg
acgaaacacc nnnnnnnnnn nnnnnnnnnn gttttagagc 360tagaaatagc
aagttaaaat aaggctagtc cgttatcaac ttgaaaaagt ggcaccgagt
420cggtgctttt tttaagcttg ggccgctcga ggtacctctc tacatatgac
atgtgagcaa 480aaggccagca aaaggccagg aaccgtaaaa aggccgcgtt
gctggcgttt ttccataggc 540tccgcccccc tgacgagcat cacaaaaatc
gacgctcaag tcagaggtgg cgaaacccga 600caggactata aagataccag
gcgtttcccc ctggaagctc cctcgtgcgc tctcctgttc 660cgaccctgcc
gcttaccgga tacctgtccg cctttctccc ttcgggaagc gtggcgcttt
720ctcatagctc acgctgtagg tatctcagtt cggtgtaggt cgttcgctcc
aagctgggct 780gtgtgcacga accccccgtt cagcccgacc gctgcgcctt
atccggtaac tatcgtcttg 840agtccaaccc ggtaagacac gacttatcgc
cactggcagc agccactggt aacaggatta 900gcagagcgag gtatgtaggc
ggtgctacag agttcttgaa gtggtggcct aactacggct 960acactagaag
aacagtattt ggtatctgcg ctctgctgaa gccagttacc ttcggaaaaa
1020gagttggtag ctcttgatcc ggcaaacaaa ccaccgctgg tagcggtggt
ttttttgttt 1080gcaagcagca gattacgcgc agaaaaaaag gatctcaaga
agatcctttg atcttttcta 1140cggggtctga cgctcagtgg aacgaaaact
cacgttaagg gattttggtc atgagattat 1200caaaaaggat cttcacctag
atccttttaa attaaaaatg aagttttaaa tcaatctaaa 1260gtatatatga
gtaaacttgg tctgacagtt accaatgctt aatcagtgag gcacctatct
1320cagcgatctg tctatttcgt tcatccatag ttgcctgact ccccgtcgtg
tagataacta 1380cgatacggga gggcttacca tctggcccca gtgctgcaat
gataccgcga gacccacgct 1440caccggctcc agatttatca gcaataaacc
agccagccgg aagggccgag cgcagaagtg 1500gtcctgcaac tttatccgcc
tccatccagt ctattaattg ttgccgggaa gctagagtaa 1560gtagttcgcc
agttaatagt ttgcgcaacg ttgttgccat tgctacaggc atcgtggtgt
1620cacgctcgtc gtttggtatg gcttcattca gctccggttc ccaacgatca
aggcgagtta 1680catgatcccc catgttgtgc aaaaaagcgg ttagctcctt
cggtcctccg atcgttgtca 1740gaagtaagtt ggccgcagtg ttatcactca
tggttatggc agcactgcat aattctctta 1800ctgtcatgcc atccgtaaga
tgcttttctg tgactggtga gtactcaacc aagtcattct 1860gagaatagtg
tatgcggcga ccgagttgct cttgcccggc gtcaatacgg gataataccg
1920cgccacatag cagaacttta aaagtgctca tcattggaaa acgttcttcg
gggcgaaaac 1980tctcaaggat cttaccgctg ttgagatcca gttcgatgta
acccactcgt gcacccaact 2040gatcttcagc atcttttact ttcaccagcg
tttctgggtg agcaaaaaca ggaaggcaaa 2100atgccgcaaa aaagggaata
agggcgacac ggaaatgttg aatactcata ctcttccttt 2160ttcaatatta
ttgaagcatt tatcagggtt attgtctcat gagcggatac atatttgaat
2220gtatttagaa aaataaacaa ataggggttc cgcgcacatt tccccgaaaa
gtgccacct 227957786DNAArtificial SequenceCMV-T7-Cas9
D10A/H840A-3xFLAG-VP64 sequence 5atatgccaag tacgccccct attgacgtca
atgacggtaa atggcccgcc tggcattatg 60cccagtacat gaccttatgg gactttccta
cttggcagta catctacgta ttagtcatcg 120ctattaccat ggtgatgcgg
ttttggcagt acatcaatgg gcgtggatag cggtttgact 180cacggggatt
tccaagtctc caccccattg acgtcaatgg gagtttgttt tggcaccaaa
240atcaacggga ctttccaaaa tgtcgtaaca actccgcccc attgacgcaa
atgggcggta 300ggcgtgtacg gtgggaggtc tatataagca gagctggttt
agtgaaccgt cagatccgct 360agagatccgc ggccgctaat acgactcact
atagggagag ccgccaccat ggataagaaa 420tactcaatag gcttagctat
cggcacaaat agcgtcggat gggcggtgat cactgatgaa 480tataaggttc
cgtctaaaaa gttcaaggtt ctgggaaata cagaccgcca cagtatcaaa
540aaaaatctta taggggctct tttatttgac agtggagaga cagcggaagc
gactcgtctc 600aaacggacag ctcgtagaag gtatacacgt cggaagaatc
gtatttgtta tctacaggag 660attttttcaa atgagatggc gaaagtagat
gatagtttct ttcatcgact tgaagagtct 720tttttggtgg aagaagacaa
gaagcatgaa cgtcatccta tttttggaaa tatagtagat 780gaagttgctt
atcatgagaa atatccaact atctatcatc tgcgaaaaaa attggtagat
840tctactgata aagcggattt gcgcttaatc tatttggcct tagcgcatat
gattaagttt 900cgtggtcatt ttttgattga gggagattta aatcctgata
atagtgatgt ggacaaacta 960tttatccagt tggtacaaac ctacaatcaa
ttatttgaag aaaaccctat taacgcaagt 1020ggagtagatg ctaaagcgat
tctttctgca cgattgagta aatcaagacg attagaaaat 1080ctcattgctc
agctccccgg tgagaagaaa aatggcttat ttgggaatct cattgctttg
1140tcattgggtt tgacccctaa ttttaaatca aattttgatt tggcagaaga
tgctaaatta 1200cagctttcaa aagatactta cgatgatgat ttagataatt
tattggcgca aattggagat 1260caatatgctg atttgttttt ggcagctaag
aatttatcag atgctatttt actttcagat 1320atcctaagag taaatactga
aataactaag gctcccctat cagcttcaat gattaaacgc 1380tacgatgaac
atcatcaaga cttgactctt ttaaaagctt tagttcgaca acaacttcca
1440gaaaagtata aagaaatctt ttttgatcaa tcaaaaaacg gatatgcagg
ttatattgat 1500gggggagcta gccaagaaga attttataaa tttatcaaac
caattttaga aaaaatggat 1560ggtactgagg aattattggt gaaactaaat
cgtgaagatt tgctgcgcaa gcaacggacc 1620tttgacaacg gctctattcc
ccatcaaatt cacttgggtg agctgcatgc tattttgaga 1680agacaagaag
acttttatcc atttttaaaa gacaatcgtg agaagattga aaaaatcttg
1740acttttcgaa ttccttatta tgttggtcca ttggcgcgtg gcaatagtcg
ttttgcatgg 1800atgactcgga agtctgaaga aacaattacc ccatggaatt
ttgaagaagt tgtcgataaa 1860ggtgcttcag ctcaatcatt tattgaacgc
atgacaaact ttgataaaaa tcttccaaat 1920gaaaaagtac taccaaaaca
tagtttgctt tatgagtatt ttacggttta taacgaattg 1980acaaaggtca
aatatgttac tgaaggaatg cgaaaaccag catttctttc aggtgaacag
2040aagaaagcca ttgttgattt actcttcaaa acaaatcgaa aagtaaccgt
taagcaatta 2100aaagaagatt atttcaaaaa aatagaatgt tttgatagtg
ttgaaatttc aggagttgaa 2160gatagattta atgcttcatt aggtacctac
catgatttgc taaaaattat taaagataaa 2220gattttttgg ataatgaaga
aaatgaagat atcttagagg atattgtttt aacattgacc 2280ttatttgaag
atagggagat gattgaggaa agacttaaaa catatgctca cctctttgat
2340gataaggtga tgaaacagct taaacgtcgc cgttatactg gttggggacg
tttgtctcga 2400aaattgatta atggtattag ggataagcaa tctggcaaaa
caatattaga ttttttgaaa 2460tcagatggtt ttgccaatcg caattttatg
cagctgatcc atgatgatag tttgacattt 2520aaagaagaca ttcaaaaagc
acaagtgtct ggacaaggcg atagtttaca tgaacatatt 2580gcaaatttag
ctggtagccc tgctattaaa aaaggtattt tacagactgt aaaagttgtt
2640gatgaattgg tcaaagtaat ggggcggcat aagccagaaa atatcgttat
tgaaatggca 2700cgtgaaaatc agacaactca aaagggccag aaaaattcgc
gagagcgtat gaaacgaatc 2760gaagaaggta tcaaagaatt aggaagtcag
attcttaaag agcatcctgt tgaaaatact 2820caattgcaaa atgaaaagct
ctatctctat tatctccaaa atggaagaga catgtatgtg 2880gaccaagaat
tagatattaa tcgtttaagt gattatgatg tcgatgccat tgttccacaa
2940agtttcctta aagacgattc aatagacaat aaggtcttaa cgcgttctga
taaaaatcgt 3000ggtaaatcgg ataacgttcc aagtgaagaa gtagtcaaaa
agatgaaaaa ctattggaga 3060caacttctaa acgccaagtt aatcactcaa
cgtaagtttg ataatttaac gaaagctgaa 3120cgtggaggtt tgagtgaact
tgataaagct ggttttatca aacgccaatt ggttgaaact 3180cgccaaatca
ctaagcatgt ggcacaaatt ttggatagtc gcatgaatac taaatacgat
3240gaaaatgata aacttattcg agaggttaaa gtgattacct taaaatctaa
attagtttct 3300gacttccgaa aagatttcca attctataaa gtacgtgaga
ttaacaatta ccatcatgcc 3360catgatgcgt atctaaatgc cgtcgttgga
actgctttga ttaagaaata tccaaaactt 3420gaatcggagt ttgtctatgg
tgattataaa gtttatgatg ttcgtaaaat gattgctaag 3480tctgagcaag
aaataggcaa agcaaccgca aaatatttct tttactctaa tatcatgaac
3540ttcttcaaaa cagaaattac acttgcaaat ggagagattc gcaaacgccc
tctaatcgaa 3600actaatgggg aaactggaga aattgtctgg gataaagggc
gagattttgc cacagtgcgc 3660aaagtattgt ccatgcccca agtcaatatt
gtcaagaaaa cagaagtaca gacaggcgga 3720ttctccaagg agtcaatttt
accaaaaaga aattcggaca agcttattgc tcgtaaaaaa 3780gactgggatc
caaaaaaata tggtggtttt gatagtccaa cggtagctta ttcagtccta
3840gtggttgcta aggtggaaaa agggaaatcg aagaagttaa aatccgttaa
agagttacta 3900gggatcacaa ttatggaaag aagttccttt gaaaaaaatc
cgattgactt tttagaagct 3960aaaggatata aggaagttaa aaaagactta
atcattaaac tacctaaata tagtcttttt 4020gagttagaaa acggtcgtaa
acggatgctg gctagtgccg gagaattaca aaaaggaaat 4080gagctggctc
tgccaagcaa atatgtgaat tttttatatt tagctagtca ttatgaaaag
4140ttgaagggta gtccagaaga taacgaacaa aaacaattgt ttgtggagca
gcataagcat 4200tatttagatg agattattga gcaaatcagt gaattttcta
agcgtgttat tttagcagat 4260gccaatttag ataaagttct tagtgcatat
aacaaacata gagacaaacc aatacgtgaa 4320caagcagaaa atattattca
tttatttacg ttgacgaatc ttggagctcc cgctgctttt 4380aaatattttg
atacaacaat tgatcgtaaa cgatatacgt ctacaaaaga agttttagat
4440gccactctta tccatcaatc catcactggt ctttatgaaa cacgcattga
tttgagtcag 4500ctaggaggtg acggttctcc caagaagaag aggaaagtct
cgagcgacta caaagaccat 4560gacggtgatt ataaagatca tgacatcgat
tacaaggatg acgatgacaa ggctgcagga 4620ggcggtggaa gcgggcgcgc
cgacgcgctg gacgatttcg atctcgacat gctgggttct 4680gatgccctcg
atgactttga cctggatatg ttgggaagcg acgcattgga tgactttgat
4740ctggacatgc tcggctccga tgctctggac gatttcgatc tcgatatgtt
ataaccggtc 4800atcatcacca tcaccattga gtttaaaccc gctgatcagc
ctcgactgtg ccttctagtt 4860gccagccatc tgttgtttgc ccctcccccg
tgccttcctt gaccctggaa ggtgccactc 4920ccactgtcct ttcctaataa
aatgaggaaa ttgcatcgca ttgtctgagt aggtgtcatt 4980ctattctggg
gggtggggtg gggcaggaca gcaaggggga ggattgggaa gacaatagca
5040ggcatgctgg ggatgcggtg ggctctatgg cttctgaggc ggaaagaacc
agctggggct 5100cgataccgtc gacctctagc tagagcttgg cgtaatcatg
gtcatagctg tttcctgtgt 5160gaaattgtta tccgctcaca attccacaca
acatacgagc cggaagcata aagtgtaaag 5220cctagggtgc ctaatgagtg
agctaactca cattaattgc gttgcgctca ctgcccgctt 5280tccagtcggg
aaacctgtcg tgccagctgc attaatgaat cggccaacgc gcggggagag
5340gcggtttgcg tattgggcgc tcttccgctt cctcgctcac tgactcgctg
cgctcggtcg 5400ttcggctgcg gcgagcggta tcagctcact caaaggcggt
aatacggtta tccacagaat 5460caggggataa cgcaggaaag aacatgtgag
caaaaggcca gcaaaaggcc aggaaccgta 5520aaaaggccgc gttgctggcg
tttttccata ggctccgccc ccctgacgag catcacaaaa 5580atcgacgctc
aagtcagagg tggcgaaacc cgacaggact ataaagatac caggcgtttc
5640cccctggaag ctccctcgtg cgctctcctg ttccgaccct gccgcttacc
ggatacctgt 5700ccgcctttct cccttcggga agcgtggcgc tttctcaatg
ctcacgctgt aggtatctca 5760gttcggtgta ggtcgttcgc tccaagctgg
gctgtgtgca cgaacccccc gttcagcccg 5820accgctgcgc cttatccggt
aactatcgtc ttgagtccaa cccggtaaga cacgacttat 5880cgccactggc
agcagccact ggtaacagga ttagcagagc gaggtatgta ggcggtgcta
5940cagagttctt gaagtggtgg cctaactacg gctacactag aaggacagta
tttggtatct 6000gcgctctgct gaagccagtt accttcggaa aaagagttgg
tagctcttga tccggcaaac 6060aaaccaccgc tggtagcggt ggtttttttg
tttgcaagca gcagattacg cgcagaaaaa 6120aaggatctca agaagatcct
ttgatctttt ctacggggtc tgacgctcag tggaacgaaa 6180actcacgtta
agggattttg gtcatgagat tatcaaaaag gatcttcacc tagatccttt
6240taaattaaaa atgaagtttt aaatcaatct aaagtatata tgagtaaact
tggtctgaca 6300gttaccaatg cttaatcagt gaggcaccta tctcagcgat
ctgtctattt cgttcatcca 6360tagttgcctg actccccgtc gtgtagataa
ctacgatacg ggagggctta ccatctggcc 6420ccagtgctgc aatgataccg
cgagacccac gctcaccggc tccagattta tcagcaataa 6480accagccagc
cggaagggcc gagcgcagaa gtggtcctgc aactttatcc gcctccatcc
6540agtctattaa ttgttgccgg gaagctagag taagtagttc gccagttaat
agtttgcgca 6600acgttgttgc cattgctaca ggcatcgtgg tgtcacgctc
gtcgtttggt atggcttcat 6660tcagctccgg ttcccaacga tcaaggcgag
ttacatgatc ccccatgttg tgcaaaaaag 6720cggttagctc cttcggtcct
ccgatcgttg tcagaagtaa gttggccgca gtgttatcac 6780tcatggttat
ggcagcactg cataattctc ttactgtcat gccatccgta agatgctttt
6840ctgtgactgg tgagtactca accaagtcat tctgagaata gtgtatgcgg
cgaccgagtt 6900gctcttgccc ggcgtcaata cgggataata ccgcgccaca
tagcagaact ttaaaagtgc 6960tcatcattgg aaaacgttct tcggggcgaa
aactctcaag gatcttaccg ctgttgagat 7020ccagttcgat gtaacccact
cgtgcaccca actgatcttc agcatctttt actttcacca 7080gcgtttctgg
gtgagcaaaa acaggaaggc aaaatgccgc aaaaaaggga ataagggcga
7140cacggaaatg ttgaatactc atactcttcc tttttcaata ttattgaagc
atttatcagg 7200gttattgtct catgagcgga tacatatttg aatgtattta
gaaaaataaa caaatagggg 7260ttccgcgcac atttccccga aaagtgccac
ctgacgtcga cggatcggga gatcgatctc 7320ccgatcccct agggtcgact
ctcagtacaa tctgctctga tgccgcatag ttaagccagt 7380atctgctccc
tgcttgtgtg ttggaggtcg ctgagtagtg cgcgagcaaa atttaagcta
7440caacaaggca aggcttgacc gacaattgca tgaagaatct gcttagggtt
aggcgttttg 7500cgctgcttcg cgatgtacgg gccagatata cgcgttgaca
ttgattattg actagttatt 7560aatagtaatc aattacgggg tcattagttc
atagcccata tatggagttc cgcgttacat 7620aacttacggt aaatggcccg
cctggctgac cgcccaacga cccccgccca ttgacgtcaa 7680taatgacgta
tgttcccata gtaacgccaa tagggacttt ccattgacgt caatgggtgg
7740actatttacg gtaaactgcc cacttggcag tacatcaagt gtatcc
778667785DNAArtificial SequenceMV-T7-Cas9 recoded
D10A/H840A-3xFLAG-VP64 sequence 6atatgccaag tacgccccct attgacgtca
atgacggtaa atggcccgcc tggcattatg 60cccagtacat gaccttatgg gactttccta
cttggcagta catctacgta ttagtcatcg 120ctattaccat ggtgatgcgg
ttttggcagt acatcaatgg gcgtggatag cggtttgact 180cacggggatt
tccaagtctc caccccattg acgtcaatgg gagtttgttt tggcaccaaa
240atcaacggga ctttccaaaa tgtcgtaaca actccgcccc attgacgcaa
atgggcggta 300ggcgtgtacg gtgggaggtc tatataagca gagctggttt
agtgaaccgt cagatccgct 360agagatccgc ggccgctaat acgactcact
atagggagag ccgccaccat ggataaaaag 420tattctattg gtttagccat
cggcactaat tccgttggat gggctgtcat aaccgatgaa 480tacaaagtac
cttcaaagaa atttaaggtg ttggggaaca cagaccgtca ttcgattaaa
540aagaatctta tcggtgccct cctattcgat agtggcgaaa cggcagaggc
gactcgcctg 600aaacgaaccg ctcggagaag gtatacacgt cgcaagaacc
gaatatgtta cttacaagaa 660atttttagca atgagatggc caaagttgac
gattctttct ttcaccgttt ggaagagtcc 720ttccttgtcg aagaggacaa
gaaacatgaa cggcacccca tctttggaaa catagtagat 780gaggtggcat
atcatgaaaa gtacccaacg atttatcacc tcagaaaaaa gctagttgac
840tcaactgata aagcggacct gaggttaatc tacttggctc ttgcccatat
gataaagttc 900cgtgggcact ttctcattga gggtgatcta aatccggaca
actcggatgt cgacaaactg 960ttcatccagt tagtacaaac ctataatcag
ttgtttgaag agaaccctat aaatgcaagt 1020ggcgtggatg cgaaggctat
tcttagcgcc cgcctctcta aatcccgacg gctagaaaac 1080ctgatcgcac
aattacccgg agagaagaaa aatgggttgt tcggtaacct tatagcgctc
1140tcactaggcc tgacaccaaa ttttaagtcg aacttcgact tagctgaaga
tgccaaattg 1200cagcttagta aggacacgta cgatgacgat ctcgacaatc
tactggcaca aattggagat 1260cagtatgcgg acttattttt ggctgccaaa
aaccttagcg atgcaatcct cctatctgac 1320atactgagag ttaatactga
gattaccaag gcgccgttat ccgcttcaat gatcaaaagg 1380tacgatgaac
atcaccaaga cttgacactt ctcaaggccc tagtccgtca gcaactgcct
1440gagaaatata aggaaatatt ctttgatcag tcgaaaaacg ggtacgcagg
ttatattgac 1500ggcggagcga gtcaagagga attctacaag tttatcaaac
ccatattaga gaagatggat 1560gggacggaag agttgcttgt aaaactcaat
cgcgaagatc tactgcgaaa gcagcggact 1620ttcgacaacg gtagcattcc
acatcaaatc cacttaggcg aattgcatgc tatacttaga 1680aggcaggagg
atttttatcc gttcctcaaa gacaatcgtg aaaagattga gaaaatccta
1740acctttcgca taccttacta tgtgggaccc ctggcccgag ggaactctcg
gttcgcatgg 1800atgacaagaa agtccgaaga aacgattact ccatggaatt
ttgaggaagt tgtcgataaa 1860ggtgcgtcag ctcaatcgtt catcgagagg
atgaccaact ttgacaagaa tttaccgaac 1920gaaaaagtat tgcctaagca
cagtttactt tacgagtatt tcacagtgta caatgaactc 1980acgaaagtta
agtatgtcac tgagggcatg cgtaaacccg cctttctaag cggagaacag
2040aagaaagcaa tagtagatct gttattcaag accaaccgca aagtgacagt
taagcaattg 2100aaagaggact actttaagaa aattgaatgc ttcgattctg
tcgagatctc cggggtagaa 2160gatcgattta atgcgtcact tggtacgtat
catgacctcc taaagataat taaagataag 2220gacttcctgg ataacgaaga
gaatgaagat atcttagaag atatagtgtt gactcttacc 2280ctctttgaag
atcgggaaat gattgaggaa agactaaaaa catacgctca cctgttcgac
2340gataaggtta tgaaacagtt aaagaggcgt cgctatacgg gctggggacg
attgtcgcgg 2400aaacttatca acgggataag agacaagcaa agtggtaaaa
ctattctcga ttttctaaag 2460agcgacggct tcgccaatag gaactttatg
cagctgatcc atgatgactc tttaaccttc 2520aaagaggata tacaaaaggc
acaggtttcc ggacaagggg actcattgca cgaacatatt 2580gcgaatcttg
ctggttcgcc agccatcaaa aagggcatac tccagacagt caaagtagtg
2640gatgagctag ttaaggtcat gggacgtcac aaaccggaaa acattgtaat
cgagatggca 2700cgcgaaaatc aaacgactca gaaggggcaa aaaaacagtc
gagagcggat gaagagaata 2760gaagagggta ttaaagaact gggcagccag
atcttaaagg agcatcctgt ggaaaatacc 2820caattgcaga acgagaaact
ttacctctat tacctacaaa atggaaggga catgtatgtt 2880gatcaggaac
tggacataaa ccgtttatct gattacgacg tcgatgccat tgtaccccaa
2940tcctttttga aggacgattc aatcgacaat aaagtgctta cacgctcgga
taagaaccga 3000gggaaaagtg acaatgttcc aagcgaggaa gtcgtaaaga
aaatgaagaa ctattggcgg 3060cagctcctaa atgcgaaact gataacgcaa
agaaagttcg ataacttaac taaagctgag 3120aggggtggct tgtctgaact
tgacaaggcc ggatttatta aacgtcagct cgtggaaacc 3180cgccaaatca
caaagcatgt tgcacagata ctagattccc gaatgaatac gaaatacgac
3240gagaacgata agctgattcg ggaagtcaaa gtaatcactt taaagtcaaa
attggtgtcg 3300gacttcagaa aggattttca attctataaa gttagggaga
taaataacta ccaccatgcg 3360cacgacgctt atcttaatgc cgtcgtaggg
accgcactca ttaagaaata cccgaagcta 3420gaaagtgagt ttgtgtatgg
tgattacaaa gtttatgacg tccgtaagat gatcgcgaaa 3480agcgaacagg
agataggcaa ggctacagcc aaatacttct tttattctaa cattatgaat
3540ttctttaaga cggaaatcac tctggcaaac ggagagatac gcaaacgacc
tttaattgaa 3600accaatgggg agacaggtga aatcgtatgg gataagggcc
gggacttcgc gacggtgaga 3660aaagttttgt ccatgcccca agtcaacata
gtaaagaaaa ctgaggtgca gaccggaggg 3720ttttcaaagg aatcgattct
tccaaaaagg aatagtgata agctcatcgc tcgtaaaaag 3780gactgggacc
cgaaaaagta cggtggcttc gatagcccta cagttgccta ttctgtccta
3840gtagtggcaa aagttgagaa gggaaaatcc aagaaactga agtcagtcaa
agaattattg 3900gggataacga ttatggagcg ctcgtctttt gaaaagaacc
ccatcgactt ccttgaggcg 3960aaaggttaca aggaagtaaa aaaggatctc
ataattaaac taccaaagta tagtctgttt 4020gagttagaaa atggccgaaa
acggatgttg gctagcgccg gagagcttca aaaggggaac 4080gaactcgcac
taccgtctaa atacgtgaat ttcctgtatt tagcgtccca ttacgagaag
4140ttgaaaggtt cacctgaaga taacgaacag aagcaacttt ttgttgagca
gcacaaacat 4200tatctcgacg aaatcataga gcaaatttcg gaattcagta
agagagtcat cctagctgat 4260gccaatctgg acaaagtatt aagcgcatac
aacaagcaca gggataaacc catacgtgag 4320caggcggaaa atattatcca
tttgtttact cttaccaacc tcggcgctcc agccgcattc 4380aagtattttg
acacaacgat agatcgcaaa cgatacactt ctaccaagga ggtgctagac
4440gcgacactga ttcaccaatc catcacggga ttatatgaaa ctcggataga
tttgtcacag 4500cttgggggtg acggatcccc caagaagaag aggaaagtct
cgagcgacta caaagaccat 4560gacggtgatt ataaagatca tgacatcgat
tacaaggatg acgatgacaa ggctgcagga 4620ggcggtggaa gcgggcgcgc
cgacgcgctg gacgatttcg atctcgacat gctgggttct 4680gatgccctcg
atgactttga cctggatatg ttgggaagcg acgcattgga tgactttgat
4740ctggacatgc tcggctccga tgctctggac gatttcgatc tcgatatgtt
ataaccggtc 4800atcatcacca tcaccattga gtttaaaccc gctgatcagc
ctcgactgtg ccttctagtt 4860gccagccatc tgttgtttgc ccctcccccg
tgccttcctt gaccctggaa ggtgccactc 4920ccactgtcct ttcctaataa
aatgaggaaa ttgcatcgca ttgtctgagt aggtgtcatt 4980ctattctggg
gggtggggtg gggcaggaca gcaaggggga ggattgggaa gacaatagca
5040ggcatgctgg ggatgcggtg ggctctatgg cttctgaggc ggaaagaacc
agctggggct 5100cgataccgtc gacctctagc tagagcttgg cgtaatcatg
gtcatagctg tttcctgtgt 5160gaaattgtta tccgctcaca attccacaca
acatacgagc cggaagcata aagtgtaaag 5220cctagggtgc ctaatgagtg
agctaactca cattaattgc gttgcgctca ctgcccgctt 5280tccagtcggg
aaacctgtcg tgccagctgc attaatgaat cggccaacgc gcggggagag
5340gcggtttgcg tattgggcgc tcttccgctt cctcgctcac tgactcgctg
cgctcggtcg 5400ttcggctgcg gcgagcggta tcagctcact caaaggcggt
aatacggtta tccacagaat 5460caggggataa cgcaggaaag aacatgtgag
caaaaggcca gcaaaaggcc aggaaccgta 5520aaaaggccgc gttgctggcg
tttttccata ggctccgccc ccctgacgag catcacaaaa 5580atcgacgctc
aagtcagagg tggcgaaacc cgacaggact ataaagatac caggcgtttc
5640cccctggaag ctccctcgtg cgctctcctg ttccgaccct gccgcttacc
ggatacctgt 5700ccgcctttct cccttcggga agcgtggcgc tttctcaatg
ctcacgctgt aggtatctca 5760gttcggtgta ggtcgttcgc tccaagctgg
gctgtgtgca cgaacccccc gttcagcccg 5820accgctgcgc cttatccggt
aactatcgtc ttgagtccaa cccggtaaga cacgacttat 5880cgccactggc
agcagccact ggtaacagga ttagcagagc gaggtatgta ggcggtgcta
5940cagagttctt gaagtggtgg cctaactacg gctacactag aaggacagta
tttggtatct 6000gcgctctgct gaagccagtt accttcggaa aaagagttgg
tagctcttga tccggcaaac 6060aaaccaccgc tggtagcggt ggtttttttg
tttgcaagca gcagattacg cgcagaaaaa 6120aaggatctca agaagatcct
ttgatctttt ctacggggtc tgacgctcag tggaacgaaa 6180actcacgtta
agggattttg gtcatgagat tatcaaaaag gatcttcacc tagatccttt
6240taaattaaaa atgaagtttt aaatcaatct aaagtatata tgagtaaact
tggtctgaca 6300gttaccaatg cttaatcagt gaggcaccta tctcagcgat
ctgtctattt cgttcatcca 6360tagttgcctg actccccgtc gtgtagataa
ctacgatacg ggagggctta ccatctggcc 6420ccagtgctgc aatgataccg
cgagacccac gctcaccggc tccagattta tcagcaataa 6480accagccagc
cggaagggcc gagcgcagaa gtggtcctgc aactttatcc gcctccatcc
6540agtctattaa ttgttgccgg gaagctagag taagtagttc gccagttaat
agtttgcgca 6600acgttgttgc cattgctaca ggcatcgtgg tgtcacgctc
gtcgtttggt atggcttcat 6660tcagctccgg ttcccaacga tcaaggcgag
ttacatgatc ccccatgttg tgcaaaaaag 6720cggttagctc cttcggtcct
ccgatcgttg tcagaagtaa gttggccgca gtgttatcac 6780tcatggttat
ggcagcactg cataattctc ttactgtcat gccatccgta agatgctttt
6840ctgtgactgg tgagtactca accaagtcat tctgagaata gtgtatgcgg
cgaccgagtt 6900gctcttgccc ggcgtcaata cgggataata ccgcgccaca
tagcagaact ttaaaagtgc 6960tcatcattgg aaaacgttct tcggggcgaa
aactctcaag gatcttaccg ctgttgagat 7020ccagttcgat gtaacccact
cgtgcaccca actgatcttc agcatctttt actttcacca 7080gcgtttctgg
gtgagcaaaa acaggaaggc aaaatgccgc aaaaaaggga ataagggcga
7140cacggaaatg ttgaatactc atactcttcc tttttcaata ttattgaagc
atttatcagg 7200gttattgtct catgagcgga tacatatttg aatgtattta
gaaaaataaa caaatagggg 7260ttccgcgcac atttccccga aaagtgccac
ctgacgtcga cggatcggga gatcgatctc 7320ccgatcccct agggtcgact
ctcagtacaa tctgctctga tgccgcatag ttaagccagt 7380atctgctccc
tgcttgtgtg ttggaggtcg ctgagtagtg cgcgagcaaa atttaagcta
7440caacaaggca aggcttgacc gacaattgca tgaagaatct gcttagggtt
aggcgttttg 7500cgctgcttcg cgatgtacgg gccagatata cgcgttgaca
ttgattattg actagttatt 7560aatagtaatc aattacgggg tcattagttc
atagcccata tatggagttc cgcgttacat 7620aacttacggt aaatggcccg
cctggctgac cgcccaacga cccccgccca ttgacgtcaa 7680taatgacgta
tgttcccata gtaacgccaa tagggacttt ccattgacgt caatgggtgg
7740actatttacg gtaaactgcc cacttggcag tacatcaagt gtatc
778571452PRTArtificial SequenceCas9-activator protein sequence 7Met
Asp Lys Lys Tyr Ser Ile Gly Leu Ala Ile Gly Thr Asn Ser Val1 5 10
15Gly Trp Ala Val Ile Thr Asp Glu Tyr Lys Val Pro Ser Lys Lys Phe
20 25 30Lys Val Leu Gly Asn Thr Asp Arg His Ser Ile Lys Lys Asn Leu
Ile 35 40 45Gly Ala Leu Leu Phe Asp Ser Gly Glu Thr Ala Glu Ala Thr
Arg Leu 50 55 60Lys Arg Thr Ala Arg Arg Arg Tyr Thr Arg Arg Lys Asn
Arg Ile Cys65 70 75 80Tyr Leu Gln Glu Ile Phe Ser Asn Glu Met Ala
Lys Val Asp Asp Ser 85 90 95Phe Phe His Arg Leu Glu Glu Ser Phe Leu
Val Glu Glu Asp Lys Lys 100 105 110His Glu Arg His Pro Ile Phe Gly
Asn Ile Val Asp Glu Val Ala Tyr 115 120 125His Glu Lys Tyr Pro Thr
Ile Tyr His Leu Arg Lys Lys Leu Val Asp 130 135 140Ser Thr Asp Lys
Ala Asp Leu Arg Leu Ile Tyr Leu Ala Leu Ala His145 150 155 160Met
Ile Lys Phe Arg Gly His Phe Leu Ile Glu Gly Asp Leu Asn Pro 165 170
175Asp Asn Ser Asp Val Asp Lys Leu Phe Ile Gln Leu Val Gln Thr Tyr
180 185 190Asn Gln Leu Phe Glu Glu Asn Pro Ile Asn Ala Ser Gly Val
Asp Ala 195 200 205Lys Ala Ile Leu Ser Ala Arg Leu Ser Lys Ser Arg
Arg Leu Glu Asn 210 215 220Leu Ile Ala Gln Leu Pro Gly Glu Lys Lys
Asn Gly Leu Phe Gly Asn225 230 235 240Leu Ile Ala Leu Ser Leu Gly
Leu Thr Pro Asn Phe Lys Ser Asn Phe 245 250 255Asp Leu Ala Glu Asp
Ala Lys Leu Gln Leu Ser Lys Asp Thr Tyr Asp 260 265 270Asp Asp Leu
Asp Asn Leu Leu Ala Gln Ile Gly Asp Gln Tyr Ala Asp 275 280 285Leu
Phe Leu Ala Ala Lys Asn Leu Ser Asp Ala Ile Leu Leu Ser Asp 290 295
300Ile Leu Arg Val Asn Thr Glu Ile Thr Lys Ala Pro Leu Ser Ala
Ser305 310 315 320Met Ile Lys Arg Tyr Asp Glu His His Gln Asp Leu
Thr Leu Leu Lys 325 330 335Ala Leu Val Arg Gln Gln Leu Pro Glu Lys
Tyr Lys Glu Ile Phe Phe 340 345 350Asp Gln Ser Lys Asn Gly Tyr Ala
Gly Tyr Ile Asp Gly Gly Ala Ser 355 360 365Gln Glu Glu Phe Tyr Lys
Phe Ile Lys Pro Ile Leu Glu Lys Met Asp 370 375 380Gly Thr Glu Glu
Leu Leu Val Lys Leu Asn Arg Glu Asp Leu Leu Arg385 390 395 400Lys
Gln Arg Thr Phe Asp Asn Gly Ser Ile Pro His Gln Ile His Leu 405 410
415Gly Glu Leu His Ala Ile Leu Arg Arg Gln Glu Asp Phe Tyr Pro Phe
420 425 430Leu Lys Asp Asn Arg Glu Lys Ile Glu Lys Ile Leu Thr Phe
Arg Ile 435 440 445Pro Tyr Tyr Val Gly Pro Leu Ala Arg Gly Asn Ser
Arg Phe Ala Trp 450 455 460Met Thr Arg Lys Ser Glu Glu Thr Ile Thr
Pro Trp Asn Phe Glu Glu465 470 475 480Val Val Asp Lys Gly Ala Ser
Ala Gln Ser Phe Ile Glu Arg Met Thr 485 490 495Asn Phe Asp Lys Asn
Leu Pro Asn Glu Lys Val Leu Pro Lys His Ser 500 505 510Leu
Leu Tyr Glu Tyr Phe Thr Val Tyr Asn Glu Leu Thr Lys Val Lys 515 520
525Tyr Val Thr Glu Gly Met Arg Lys Pro Ala Phe Leu Ser Gly Glu Gln
530 535 540Lys Lys Ala Ile Val Asp Leu Leu Phe Lys Thr Asn Arg Lys
Val Thr545 550 555 560Val Lys Gln Leu Lys Glu Asp Tyr Phe Lys Lys
Ile Glu Cys Phe Asp 565 570 575Ser Val Glu Ile Ser Gly Val Glu Asp
Arg Phe Asn Ala Ser Leu Gly 580 585 590Thr Tyr His Asp Leu Leu Lys
Ile Ile Lys Asp Lys Asp Phe Leu Asp 595 600 605Asn Glu Glu Asn Glu
Asp Ile Leu Glu Asp Ile Val Leu Thr Leu Thr 610 615 620Leu Phe Glu
Asp Arg Glu Met Ile Glu Glu Arg Leu Lys Thr Tyr Ala625 630 635
640His Leu Phe Asp Asp Lys Val Met Lys Gln Leu Lys Arg Arg Arg Tyr
645 650 655Thr Gly Trp Gly Arg Leu Ser Arg Lys Leu Ile Asn Gly Ile
Arg Asp 660 665 670Lys Gln Ser Gly Lys Thr Ile Leu Asp Phe Leu Lys
Ser Asp Gly Phe 675 680 685Ala Asn Arg Asn Phe Met Gln Leu Ile His
Asp Asp Ser Leu Thr Phe 690 695 700Lys Glu Asp Ile Gln Lys Ala Gln
Val Ser Gly Gln Gly Asp Ser Leu705 710 715 720His Glu His Ile Ala
Asn Leu Ala Gly Ser Pro Ala Ile Lys Lys Gly 725 730 735Ile Leu Gln
Thr Val Lys Val Val Asp Glu Leu Val Lys Val Met Gly 740 745 750Arg
His Lys Pro Glu Asn Ile Val Ile Glu Met Ala Arg Glu Asn Gln 755 760
765Thr Thr Gln Lys Gly Gln Lys Asn Ser Arg Glu Arg Met Lys Arg Ile
770 775 780Glu Glu Gly Ile Lys Glu Leu Gly Ser Gln Ile Leu Lys Glu
His Pro785 790 795 800Val Glu Asn Thr Gln Leu Gln Asn Glu Lys Leu
Tyr Leu Tyr Tyr Leu 805 810 815Gln Asn Gly Arg Asp Met Tyr Val Asp
Gln Glu Leu Asp Ile Asn Arg 820 825 830Leu Ser Asp Tyr Asp Val Asp
Ala Ile Val Pro Gln Ser Phe Leu Lys 835 840 845Asp Asp Ser Ile Asp
Asn Lys Val Leu Thr Arg Ser Asp Lys Asn Arg 850 855 860Gly Lys Ser
Asp Asn Val Pro Ser Glu Glu Val Val Lys Lys Met Lys865 870 875
880Asn Tyr Trp Arg Gln Leu Leu Asn Ala Lys Leu Ile Thr Gln Arg Lys
885 890 895Phe Asp Asn Leu Thr Lys Ala Glu Arg Gly Gly Leu Ser Glu
Leu Asp 900 905 910Lys Ala Gly Phe Ile Lys Arg Gln Leu Val Glu Thr
Arg Gln Ile Thr 915 920 925Lys His Val Ala Gln Ile Leu Asp Ser Arg
Met Asn Thr Lys Tyr Asp 930 935 940Glu Asn Asp Lys Leu Ile Arg Glu
Val Lys Val Ile Thr Leu Lys Ser945 950 955 960Lys Leu Val Ser Asp
Phe Arg Lys Asp Phe Gln Phe Tyr Lys Val Arg 965 970 975Glu Ile Asn
Asn Tyr His His Ala His Asp Ala Tyr Leu Asn Ala Val 980 985 990Val
Gly Thr Ala Leu Ile Lys Lys Tyr Pro Lys Leu Glu Ser Glu Phe 995
1000 1005Val Tyr Gly Asp Tyr Lys Val Tyr Asp Val Arg Lys Met Ile
Ala Lys 1010 1015 1020Ser Glu Gln Glu Ile Gly Lys Ala Thr Ala Lys
Tyr Phe Phe Tyr Ser1025 1030 1035 1040Asn Ile Met Asn Phe Phe Lys
Thr Glu Ile Thr Leu Ala Asn Gly Glu 1045 1050 1055Ile Arg Lys Arg
Pro Leu Ile Glu Thr Asn Gly Glu Thr Gly Glu Ile 1060 1065 1070Val
Trp Asp Lys Gly Arg Asp Phe Ala Thr Val Arg Lys Val Leu Ser 1075
1080 1085Met Pro Gln Val Asn Ile Val Lys Lys Thr Glu Val Gln Thr
Gly Gly 1090 1095 1100Phe Ser Lys Glu Ser Ile Leu Pro Lys Arg Asn
Ser Asp Lys Leu Ile1105 1110 1115 1120Ala Arg Lys Lys Asp Trp Asp
Pro Lys Lys Tyr Gly Gly Phe Asp Ser 1125 1130 1135Pro Thr Val Ala
Tyr Ser Val Leu Val Val Ala Lys Val Glu Lys Gly 1140 1145 1150Lys
Ser Lys Lys Leu Lys Ser Val Lys Glu Leu Leu Gly Ile Thr Ile 1155
1160 1165Met Glu Arg Ser Ser Phe Glu Lys Asn Pro Ile Asp Phe Leu
Glu Ala 1170 1175 1180Lys Gly Tyr Lys Glu Val Lys Lys Asp Leu Ile
Ile Lys Leu Pro Lys1185 1190 1195 1200Tyr Ser Leu Phe Glu Leu Glu
Asn Gly Arg Lys Arg Met Leu Ala Ser 1205 1210 1215Ala Gly Glu Leu
Gln Lys Gly Asn Glu Leu Ala Leu Pro Ser Lys Tyr 1220 1225 1230Val
Asn Phe Leu Tyr Leu Ala Ser His Tyr Glu Lys Leu Lys Gly Ser 1235
1240 1245Pro Glu Asp Asn Glu Gln Lys Gln Leu Phe Val Glu Gln His
Lys His 1250 1255 1260Tyr Leu Asp Glu Ile Ile Glu Gln Ile Ser Glu
Phe Ser Lys Arg Val1265 1270 1275 1280Ile Leu Ala Asp Ala Asn Leu
Asp Lys Val Leu Ser Ala Tyr Asn Lys 1285 1290 1295His Arg Asp Lys
Pro Ile Arg Glu Gln Ala Glu Asn Ile Ile His Leu 1300 1305 1310Phe
Thr Leu Thr Asn Leu Gly Ala Pro Ala Ala Phe Lys Tyr Phe Asp 1315
1320 1325Thr Thr Ile Asp Arg Lys Arg Tyr Thr Ser Thr Lys Glu Val
Leu Asp 1330 1335 1340Ala Thr Leu Ile His Gln Ser Ile Thr Gly Leu
Tyr Glu Thr Arg Ile1345 1350 1355 1360Asp Leu Ser Gln Leu Gly Gly
Asp Gly Ser Asp Tyr Lys Asp His Asp 1365 1370 1375Gly Asp Tyr Lys
Asp His Asp Ile Asp Tyr Lys Asp Asp Asp Asp Lys 1380 1385 1390Ala
Ala Gly Gly Gly Gly Ser Gly Arg Ala Asp Ala Leu Asp Asp Phe 1395
1400 1405Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe Asp
Leu Asp 1410 1415 1420Met Leu Gly Ser Asp Ala Leu Asp Asp Phe Asp
Leu Asp Met Leu Gly1425 1430 1435 1440Ser Asp Ala Leu Asp Asp Phe
Asp Leu Asp Met Leu 1445 1450
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