ATG4C_HUMAN
ID ATG4C_HUMAN Reviewed; 458 AA.
AC Q96DT6; A6NLR8; D3DQ58; Q96K04;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=Cysteine protease ATG4C {ECO:0000305};
DE EC=3.4.22.- {ECO:0000269|PubMed:21177865};
DE AltName: Full=AUT-like 3 cysteine endopeptidase;
DE AltName: Full=Autophagy-related cysteine endopeptidase 3 {ECO:0000303|PubMed:12446702};
DE Short=Autophagin-3 {ECO:0000303|PubMed:12446702};
DE AltName: Full=Autophagy-related protein 4 homolog C {ECO:0000303|PubMed:21177865};
DE Short=HsAPG4C {ECO:0000303|PubMed:29458288};
GN Name=ATG4C {ECO:0000303|PubMed:21177865, ECO:0000312|HGNC:HGNC:16040};
GN Synonyms=APG4C {ECO:0000303|Ref.3}, AUTL1,
GN AUTL3 {ECO:0000312|HGNC:HGNC:16040};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP RETRACTED PAPER.
RC TISSUE=Brain;
RX PubMed=12446702; DOI=10.1074/jbc.m208247200;
RA Marino G., Uria J.A., Puente X.S., Quesada V., Bordallo J., Lopez-Otin C.;
RT "Human autophagins, a family of cysteine proteinases potentially implicated
RT in cell degradation by autophagy.";
RL J. Biol. Chem. 278:3671-3678(2003).
RN [2]
RP RETRACTION NOTICE OF PUBMED:12446702.
RX PubMed=30808002; DOI=10.1074/jbc.w118.007325;
RA Marino G., Uria J.A., Puente X.S., Quesada V., Bordallo J., Lopez-Otin C.;
RL J. Biol. Chem. 294:1431-1431(2019).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Heart;
RA Chen J.M., Barrett A.J.;
RT "Cloning and sequencing of a human homologue of the yeast Apg4 cysteine
RT endopeptidase involved in autophagy.";
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [9]
RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY REGULATION.
RX PubMed=21177865; DOI=10.1074/jbc.m110.199059;
RA Li M., Hou Y., Wang J., Chen X., Shao Z.M., Yin X.M.;
RT "Kinetics comparisons of mammalian Atg4 homologues indicate selective
RT preferences toward diverse Atg8 substrates.";
RL J. Biol. Chem. 286:7327-7338(2011).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-451 AND THR-452, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [11]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=29458288; DOI=10.1080/15548627.2018.1437341;
RA Kauffman K.J., Yu S., Jin J., Mugo B., Nguyen N., O'Brien A., Nag S.,
RA Lystad A.H., Melia T.J.;
RT "Delipidation of mammalian Atg8-family proteins by each of the four ATG4
RT proteases.";
RL Autophagy 14:992-1010(2018).
RN [12]
RP FUNCTION.
RX PubMed=30661429; DOI=10.1080/15548627.2019.1569925;
RA Agrotis A., Pengo N., Burden J.J., Ketteler R.;
RT "Redundancy of human ATG4 protease isoforms in autophagy and LC3/GABARAP
RT processing revealed in cells.";
RL Autophagy 15:976-997(2019).
RN [13]
RP FUNCTION.
RX PubMed=33773106; DOI=10.1016/j.molcel.2021.03.001;
RA Nguyen T.N., Padman B.S., Zellner S., Khuu G., Uoselis L., Lam W.K.,
RA Skulsuppaisarn M., Lindblom R.S.J., Watts E.M., Behrends C., Lazarou M.;
RT "ATG4 family proteins drive phagophore growth independently of the
RT LC3/GABARAP lipidation system.";
RL Mol. Cell 81:2013-2030(2021).
RN [14]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=33909989; DOI=10.1016/j.molcel.2021.03.020;
RA Durgan J., Lystad A.H., Sloan K., Carlsson S.R., Wilson M.I., Marcassa E.,
RA Ulferts R., Webster J., Lopez-Clavijo A.F., Wakelam M.J., Beale R.,
RA Simonsen A., Oxley D., Florey O.;
RT "Non-canonical autophagy drives alternative ATG8 conjugation to
RT phosphatidylserine.";
RL Mol. Cell 81:2031-2040(2021).
CC -!- FUNCTION: Cysteine protease that plays a key role in autophagy by
CC mediating both proteolytic activation and delipidation of ATG8 family
CC proteins (PubMed:21177865, PubMed:29458288, PubMed:30661429). The
CC protease activity is required for proteolytic activation of ATG8 family
CC proteins: cleaves the C-terminal amino acid of ATG8 proteins MAP1LC3
CC and GABARAPL2, to reveal a C-terminal glycine (PubMed:21177865).
CC Exposure of the glycine at the C-terminus is essential for ATG8
CC proteins conjugation to phosphatidylethanolamine (PE) and insertion to
CC membranes, which is necessary for autophagy (By similarity). In
CC addition to the protease activity, also mediates delipidation of ATG8
CC family proteins (PubMed:29458288, PubMed:33909989). Catalyzes
CC delipidation of PE-conjugated forms of ATG8 proteins during
CC macroautophagy (PubMed:29458288, PubMed:33909989). Compared to ATG4B,
CC the major protein for proteolytic activation of ATG8 proteins, shows
CC weaker ability to cleave the C-terminal amino acid of ATG8 proteins,
CC while it displays stronger delipidation activity (PubMed:29458288). In
CC contrast to other members of the family, weakly or not involved in
CC phagophore growth during mitophagy (PubMed:33773106).
CC {ECO:0000250|UniProtKB:Q9Y4P1, ECO:0000269|PubMed:21177865,
CC ECO:0000269|PubMed:29458288, ECO:0000269|PubMed:30661429,
CC ECO:0000269|PubMed:33773106, ECO:0000269|PubMed:33909989}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[protein]-C-terminal L-amino acid-glycyl-
CC phosphatidylethanolamide + H2O = [protein]-C-terminal L-amino acid-
CC glycine + a 1,2-diacyl-sn-glycero-3-phosphoethanolamine;
CC Xref=Rhea:RHEA:67548, Rhea:RHEA-COMP:17323, Rhea:RHEA-COMP:17324,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:64612, ChEBI:CHEBI:172940,
CC ChEBI:CHEBI:172941; Evidence={ECO:0000269|PubMed:29458288,
CC ECO:0000269|PubMed:33909989};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67549;
CC Evidence={ECO:0000269|PubMed:29458288, ECO:0000269|PubMed:33909989};
CC -!- ACTIVITY REGULATION: Inhibited by N-ethylmaleimide.
CC {ECO:0000269|PubMed:21177865}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=47.5 uM for MAP1LC3B {ECO:0000269|PubMed:21177865};
CC KM=12.4 uM for GABARAPL2 {ECO:0000269|PubMed:21177865};
CC -!- INTERACTION:
CC Q96DT6; P42858: HTT; NbExp=15; IntAct=EBI-3225845, EBI-466029;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q8BGE6}.
CC -!- SIMILARITY: Belongs to the peptidase C54 family. {ECO:0000305}.
CC -!- CAUTION: A paper describing ATG4C tissue expression and activity has
CC been retracted, due to concerns of image duplication in some of the
CC figures. {ECO:0000269|PubMed:12446702, ECO:0000305|PubMed:30808002}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB55356.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AJ312234; CAC85556.1; -; mRNA.
DR EMBL; AJ320169; CAC43939.1; -; mRNA.
DR EMBL; AK027773; BAB55356.1; ALT_FRAME; mRNA.
DR EMBL; AC103923; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471059; EAX06579.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX06580.1; -; Genomic_DNA.
DR EMBL; BC033024; AAH33024.1; -; mRNA.
DR CCDS; CCDS623.1; -.
DR RefSeq; NP_116241.2; NM_032852.3.
DR RefSeq; NP_835739.1; NM_178221.2.
DR RefSeq; XP_005271345.1; XM_005271288.2.
DR AlphaFoldDB; Q96DT6; -.
DR SMR; Q96DT6; -.
DR BioGRID; 124372; 37.
DR IntAct; Q96DT6; 14.
DR STRING; 9606.ENSP00000322159; -.
DR MEROPS; C54.004; -.
DR GlyGen; Q96DT6; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q96DT6; -.
DR PhosphoSitePlus; Q96DT6; -.
DR BioMuta; ATG4C; -.
DR DMDM; 61211867; -.
DR EPD; Q96DT6; -.
DR jPOST; Q96DT6; -.
DR MassIVE; Q96DT6; -.
DR MaxQB; Q96DT6; -.
DR PaxDb; Q96DT6; -.
DR PeptideAtlas; Q96DT6; -.
DR PRIDE; Q96DT6; -.
DR ProteomicsDB; 76320; -.
DR Antibodypedia; 1971; 613 antibodies from 38 providers.
DR DNASU; 84938; -.
DR Ensembl; ENST00000317868.9; ENSP00000322159.4; ENSG00000125703.15.
DR Ensembl; ENST00000371120.7; ENSP00000360161.3; ENSG00000125703.15.
DR GeneID; 84938; -.
DR KEGG; hsa:84938; -.
DR MANE-Select; ENST00000317868.9; ENSP00000322159.4; NM_032852.4; NP_116241.2.
DR UCSC; uc001dat.5; human.
DR CTD; 84938; -.
DR DisGeNET; 84938; -.
DR GeneCards; ATG4C; -.
DR HGNC; HGNC:16040; ATG4C.
DR HPA; ENSG00000125703; Tissue enriched (brain).
DR MIM; 611339; gene.
DR neXtProt; NX_Q96DT6; -.
DR OpenTargets; ENSG00000125703; -.
DR PharmGKB; PA25183; -.
DR VEuPathDB; HostDB:ENSG00000125703; -.
DR eggNOG; KOG2674; Eukaryota.
DR GeneTree; ENSGT00530000063000; -.
DR HOGENOM; CLU_021259_3_2_1; -.
DR InParanoid; Q96DT6; -.
DR OMA; KMAGDWY; -.
DR OrthoDB; 431748at2759; -.
DR PhylomeDB; Q96DT6; -.
DR TreeFam; TF314847; -.
DR PathwayCommons; Q96DT6; -.
DR Reactome; R-HSA-1632852; Macroautophagy.
DR SABIO-RK; Q96DT6; -.
DR SignaLink; Q96DT6; -.
DR BioGRID-ORCS; 84938; 16 hits in 1073 CRISPR screens.
DR ChiTaRS; ATG4C; human.
DR GenomeRNAi; 84938; -.
DR Pharos; Q96DT6; Tbio.
DR PRO; PR:Q96DT6; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q96DT6; protein.
DR Bgee; ENSG00000125703; Expressed in corpus callosum and 174 other tissues.
DR ExpressionAtlas; Q96DT6; baseline and differential.
DR Genevisible; Q96DT6; HS.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IEA:InterPro.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IDA:UniProtKB.
DR GO; GO:0006914; P:autophagy; IDA:UniProtKB.
DR GO; GO:0051697; P:protein delipidation; IDA:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR InterPro; IPR032915; ATG4C.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR005078; Peptidase_C54.
DR PANTHER; PTHR22624; PTHR22624; 1.
DR PANTHER; PTHR22624:SF38; PTHR22624:SF38; 1.
DR Pfam; PF03416; Peptidase_C54; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
PE 1: Evidence at protein level;
KW Acetylation; Autophagy; Cytoplasm; Hydrolase; Phosphoprotein; Protease;
KW Protein transport; Reference proteome; Thiol protease; Transport;
KW Ubl conjugation pathway.
FT CHAIN 1..458
FT /note="Cysteine protease ATG4C"
FT /id="PRO_0000215849"
FT ACT_SITE 111
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 345
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 347
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0007744|PubMed:19413330"
FT MOD_RES 451
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 452
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
SQ SEQUENCE 458 AA; 52497 MW; 6A23A05E7F20AF27 CRC64;
MEATGTDEVD KLKTKFISAW NNMKYSWVLK TKTYFSRNSP VLLLGKCYHF KYEDEDKTLP
AESGCTIEDH VIAGNVEEFR KDFISRIWLT YREEFPQIEG SALTTDCGWG CTLRTGQMLL
AQGLILHFLG RAWTWPDALN IENSDSESWT SHTVKKFTAS FEASLSGERE FKTPTISLKE
TIGKYSDDHE MRNEVYHRKI ISWFGDSPLA LFGLHQLIEY GKKSGKKAGD WYGPAVVAHI
LRKAVEEARH PDLQGITIYV AQDCTVYNSD VIDKQSASMT SDNADDKAVI ILVPVRLGGE
RTNTDYLEFV KGILSLEYCV GIIGGKPKQS YYFAGFQDDS LIYMDPHYCQ SFVDVSIKDF
PLETFHCPSP KKMSFRKMDP SCTIGFYCRN VQDFKRASEE ITKMLKFSSK EKYPLFTFVN
GHSRDYDFTS TTTNEEDLFS EDEKKQLKRF STEEFVLL
