F264_HUMAN
ID F264_HUMAN Reviewed; 469 AA.
AC Q16877; Q5S3G5; Q5XLC2; Q64EX5;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 6.
DT 03-AUG-2022, entry version 195.
DE RecName: Full=6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4;
DE Short=6PF-2-K/Fru-2,6-P2ase 4;
DE Short=PFK/FBPase 4;
DE AltName: Full=6PF-2-K/Fru-2,6-P2ase testis-type isozyme;
DE Includes:
DE RecName: Full=6-phosphofructo-2-kinase;
DE EC=2.7.1.105;
DE Includes:
DE RecName: Full=Fructose-2,6-bisphosphatase;
DE EC=3.1.3.46;
GN Name=PFKFB4;
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 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), AND ALTERNATIVE SPLICING.
RX PubMed=15474002; DOI=10.1016/j.febslet.2004.08.053;
RA Minchenko O., Opentanova I., Minchenko D., Ogura T., Esumi H.;
RT "Hypoxia induces transcription of 6-phosphofructo-2-kinase/fructose-2,6-
RT biphosphatase-4 gene via hypoxia-inducible factor-1alpha activation.";
RL FEBS Lett. 576:14-20(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Sakakibara R.;
RL Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND ALTERNATIVE SPLICING.
RA Minchenko O.H., Opentanova I.L., Minchenko D.O., Kurashima Y., Esumi H.;
RT "Alternative splicing of human 6-phosphofructo-2-kinase/fructose-2,6-
RT phosphatase 4 in melanoma cells.";
RL Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=10095107; DOI=10.1016/s0378-1119(99)00037-2;
RA Manzano A., Perez J.X., Nadal M., Estivill X., Lange A., Bartrons R.;
RT "Cloning, expression and chromosomal localization of a human testis 6-
RT phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene.";
RL Gene 229:83-89(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=15642344; DOI=10.1016/j.febslet.2004.11.096;
RA Gomez M., Manzano A., Navarro-Sabate A., Duran J., Obach M., Perales J.C.,
RA Bartrons R.;
RT "Specific expression of pfkfb4 gene in spermatogonia germ cells and
RT analysis of its 5'-flanking region.";
RL FEBS Lett. 579:357-362(2005).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [7]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 357-469 (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=8830046; DOI=10.1093/oxfordjournals.jbchem.a021270;
RA Sakai A., Kato M., Fukasawa M., Ishiguro M., Furuya E., Sakakibara R.;
RT "Cloning of cDNA encoding for a novel isozyme of fructose 6-phosphate, 2-
RT kinase/fructose 2,6-bisphosphatase from human placenta.";
RL J. Biochem. 119:506-511(1996).
RN [10]
RP VARIANT [LARGE SCALE ANALYSIS] LYS-181.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Synthesis and degradation of fructose 2,6-bisphosphate.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=beta-D-fructose 2,6-bisphosphate + H2O = beta-D-fructose 6-
CC phosphate + phosphate; Xref=Rhea:RHEA:17289, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:57634, ChEBI:CHEBI:58579; EC=3.1.3.46;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + beta-D-fructose 6-phosphate = ADP + beta-D-fructose 2,6-
CC bisphosphate + H(+); Xref=Rhea:RHEA:15653, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:57634, ChEBI:CHEBI:58579,
CC ChEBI:CHEBI:456216; EC=2.7.1.105;
CC -!- ACTIVITY REGULATION: The most important regulatory mechanism of these
CC opposing activities is by phosphorylation and dephosphorylation of the
CC enzyme. {ECO:0000250}.
CC -!- SUBUNIT: Homodimer. {ECO:0000250}.
CC -!- INTERACTION:
CC Q16877; Q68D86: CCDC102B; NbExp=3; IntAct=EBI-764534, EBI-10171570;
CC Q16877; Q9UJX2: CDC23; NbExp=3; IntAct=EBI-764534, EBI-396137;
CC Q16877; Q96L50: LRR1; NbExp=3; IntAct=EBI-764534, EBI-2510106;
CC Q16877; P16118: PFKFB1; NbExp=5; IntAct=EBI-764534, EBI-709807;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q16877-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q16877-2; Sequence=VSP_056530;
CC Name=3;
CC IsoId=Q16877-3; Sequence=VSP_056621;
CC -!- SIMILARITY: In the C-terminal section; belongs to the phosphoglycerate
CC mutase family. {ECO:0000305}.
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DR EMBL; AY756062; AAV28717.1; -; mRNA.
DR EMBL; AY756064; AAV28719.1; -; mRNA.
DR EMBL; D49818; BAA18921.1; -; mRNA.
DR EMBL; AY714243; AAU14998.1; -; mRNA.
DR EMBL; AF108765; AAD09427.1; -; mRNA.
DR EMBL; AY786551; AAV65753.1; -; Genomic_DNA.
DR EMBL; AC134772; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471055; EAW64890.1; -; Genomic_DNA.
DR EMBL; BC010269; AAH10269.1; -; mRNA.
DR CCDS; CCDS2771.1; -. [Q16877-1]
DR CCDS; CCDS82769.1; -. [Q16877-2]
DR PIR; JC5871; JC5871.
DR RefSeq; NP_001304063.1; NM_001317134.1.
DR RefSeq; NP_001304064.1; NM_001317135.1.
DR RefSeq; NP_001304065.1; NM_001317136.1.
DR RefSeq; NP_001304066.1; NM_001317137.1. [Q16877-2]
DR RefSeq; NP_001304067.1; NM_001317138.1.
DR RefSeq; NP_004558.1; NM_004567.3. [Q16877-1]
DR AlphaFoldDB; Q16877; -.
DR SMR; Q16877; -.
DR BioGRID; 111231; 32.
DR ComplexPortal; CPX-1996; 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 complex.
DR IntAct; Q16877; 13.
DR MINT; Q16877; -.
DR STRING; 9606.ENSP00000232375; -.
DR BindingDB; Q16877; -.
DR ChEMBL; CHEMBL3721311; -.
DR DrugBank; DB04493; Fructose-6-phosphate.
DR DrugBank; DB04395; Phosphoaminophosphonic Acid-Adenylate Ester.
DR DEPOD; PFKFB4; -.
DR iPTMnet; Q16877; -.
DR PhosphoSitePlus; Q16877; -.
DR BioMuta; PFKFB4; -.
DR DMDM; 6226609; -.
DR EPD; Q16877; -.
DR jPOST; Q16877; -.
DR MassIVE; Q16877; -.
DR MaxQB; Q16877; -.
DR PaxDb; Q16877; -.
DR PeptideAtlas; Q16877; -.
DR PRIDE; Q16877; -.
DR ProteomicsDB; 61116; -. [Q16877-1]
DR ProteomicsDB; 65838; -.
DR ProteomicsDB; 65916; -.
DR Antibodypedia; 30130; 193 antibodies from 24 providers.
DR DNASU; 5210; -.
DR Ensembl; ENST00000232375.8; ENSP00000232375.3; ENSG00000114268.12. [Q16877-1]
DR Ensembl; ENST00000383734.6; ENSP00000373240.2; ENSG00000114268.12. [Q16877-2]
DR GeneID; 5210; -.
DR KEGG; hsa:5210; -.
DR MANE-Select; ENST00000232375.8; ENSP00000232375.3; NM_004567.4; NP_004558.1.
DR UCSC; uc003ctv.4; human. [Q16877-1]
DR CTD; 5210; -.
DR DisGeNET; 5210; -.
DR GeneCards; PFKFB4; -.
DR HGNC; HGNC:8875; PFKFB4.
DR HPA; ENSG00000114268; Tissue enhanced (testis).
DR MIM; 605320; gene.
DR neXtProt; NX_Q16877; -.
DR OpenTargets; ENSG00000114268; -.
DR PharmGKB; PA33214; -.
DR VEuPathDB; HostDB:ENSG00000114268; -.
DR eggNOG; KOG0234; Eukaryota.
DR GeneTree; ENSGT00950000182835; -.
DR HOGENOM; CLU_006383_1_1_1; -.
DR InParanoid; Q16877; -.
DR OMA; IACMNGR; -.
DR OrthoDB; 392001at2759; -.
DR PhylomeDB; Q16877; -.
DR TreeFam; TF313541; -.
DR BioCyc; MetaCyc:HS03750-MON; -.
DR BRENDA; 2.7.1.105; 2681.
DR BRENDA; 3.1.3.46; 2681.
DR PathwayCommons; Q16877; -.
DR Reactome; R-HSA-9634600; Regulation of glycolysis by fructose 2,6-bisphosphate metabolism.
DR SignaLink; Q16877; -.
DR SIGNOR; Q16877; -.
DR BioGRID-ORCS; 5210; 21 hits in 1075 CRISPR screens.
DR ChiTaRS; PFKFB4; human.
DR GeneWiki; PFKFB4; -.
DR GenomeRNAi; 5210; -.
DR Pharos; Q16877; Tchem.
DR PRO; PR:Q16877; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q16877; protein.
DR Bgee; ENSG00000114268; Expressed in blood and 118 other tissues.
DR ExpressionAtlas; Q16877; baseline and differential.
DR Genevisible; Q16877; HS.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0003873; F:6-phosphofructo-2-kinase activity; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004331; F:fructose-2,6-bisphosphate 2-phosphatase activity; IBA:GO_Central.
DR GO; GO:0006003; P:fructose 2,6-bisphosphate metabolic process; IBA:GO_Central.
DR GO; GO:0006000; P:fructose metabolic process; IEA:InterPro.
DR CDD; cd07067; HP_PGM_like; 1.
DR Gene3D; 3.40.50.1240; -; 1.
DR Gene3D; 3.40.50.300; -; 1.
DR InterPro; IPR003094; 6Pfruct_kin.
DR InterPro; IPR013079; 6Phosfructo_kin.
DR InterPro; IPR013078; His_Pase_superF_clade-1.
DR InterPro; IPR029033; His_PPase_superfam.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR001345; PG/BPGM_mutase_AS.
DR PANTHER; PTHR10606; PTHR10606; 1.
DR Pfam; PF01591; 6PF2K; 1.
DR Pfam; PF00300; His_Phos_1; 1.
DR PRINTS; PR00991; 6PFRUCTKNASE.
DR SMART; SM00855; PGAM; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR SUPFAM; SSF53254; SSF53254; 1.
DR PROSITE; PS00175; PG_MUTASE; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Hydrolase; Kinase;
KW Multifunctional enzyme; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Transferase.
FT CHAIN 1..469
FT /note="6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
FT 4"
FT /id="PRO_0000179970"
FT REGION 1..249
FT /note="6-phosphofructo-2-kinase"
FT REGION 250..469
FT /note="Fructose-2,6-bisphosphatase"
FT ACT_SITE 129
FT /evidence="ECO:0000255"
FT ACT_SITE 159
FT /evidence="ECO:0000255"
FT ACT_SITE 257
FT /note="Tele-phosphohistidine intermediate"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT ACT_SITE 326
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT BINDING 46..54
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q16875"
FT BINDING 79
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000250|UniProtKB:Q16875"
FT BINDING 103
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000250|UniProtKB:Q16875"
FT BINDING 131
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000250|UniProtKB:Q16875"
FT BINDING 137
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000250|UniProtKB:Q16875"
FT BINDING 168..173
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q16875"
FT BINDING 173
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000250|UniProtKB:Q16875"
FT BINDING 194
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000250|UniProtKB:Q16875"
FT BINDING 198
FT /ligand="beta-D-fructose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:57634"
FT /evidence="ECO:0000250|UniProtKB:Q16875"
FT BINDING 256
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000250|UniProtKB:Q16875"
FT BINDING 263
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000250|UniProtKB:Q16875"
FT BINDING 269
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT BINDING 306
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000250|UniProtKB:Q16875"
FT BINDING 337
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT BINDING 348..351
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT BINDING 351
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT BINDING 355
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT BINDING 366
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT BINDING 392..396
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT BINDING 392
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT BINDING 396
FT /ligand="beta-D-fructose 2,6-bisphosphate"
FT /ligand_id="ChEBI:CHEBI:58579"
FT /evidence="ECO:0000250|UniProtKB:P07953"
FT BINDING 428
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q16875"
FT SITE 391
FT /note="Transition state stabilizer"
FT /evidence="ECO:0000250|UniProtKB:P00950"
FT MOD_RES 444
FT /note="Phosphothreonine; by PKC"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..34
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15474002, ECO:0000303|Ref.3"
FT /id="VSP_056621"
FT VAR_SEQ 330..364
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15474002"
FT /id="VSP_056530"
FT VARIANT 181
FT /note="N -> K (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036075"
SQ SEQUENCE 469 AA; 54040 MW; 7E190C3C0A197D9F CRC64;
MASPRELTQN PLKKIWMPYS NGRPALHACQ RGVCMTNCPT LIVMVGLPAR GKTYISKKLT
RYLNWIGVPT REFNVGQYRR DVVKTYKSFE FFLPDNEEGL KIRKQCALAA LRDVRRFLSE
EGGHVAVFDA TNTTRERRAT IFNFGEQNGY KTFFVESICV DPEVIAANIV QVKLGSPDYV
NRDSDEATED FMRRIECYEN SYESLDEDLD RDLSYIKIMD VGQSYVVNRV ADHIQSRIVY
YLMNIHVTPR SIYLCRHGES ELNLKGRIGG DPGLSPRGRE FAKSLAQFIS DQNIKDLKVW
TSQMKRTIQT AEALGVPYEQ WKVLNEIDAG VCEEMTYEEI QDNYPLEFAL RDQDKYRYRY
PKGESYEDLV QRLEPVIMEL ERQENVLVIC HQAVMRCLLA YFLDKAAEQL PYLKCPLHTV
LKLTPVAYGC KVESIFLNVA AVNTHRDRPQ NVDISRPPEE ALVTVPAHQ