L_CCHFI
ID L_CCHFI Reviewed; 3945 AA.
AC Q6TQR6; Q6TFZ7; Q6TQF5;
DT 10-AUG-2010, integrated into UniProtKB/Swiss-Prot.
DT 03-AUG-2022, sequence version 3.
DT 03-AUG-2022, entry version 92.
DE RecName: Full=RNA-directed RNA polymerase L;
DE Short=Protein L;
DE AltName: Full=Large structural protein;
DE AltName: Full=Replicase;
DE AltName: Full=Transcriptase;
DE Includes:
DE RecName: Full=Ubiquitinyl hydrolase;
DE EC=3.4.19.12 {ECO:0000269|PubMed:18078692, ECO:0000269|PubMed:21228232, ECO:0000269|PubMed:21266548, ECO:0000269|PubMed:28877473};
DE EC=3.4.22.- {ECO:0000269|PubMed:21228232, ECO:0000269|PubMed:28877473};
DE Includes:
DE RecName: Full=cap-snatching endonuclease;
DE EC=3.1.-.- {ECO:0000250|UniProtKB:Q6GWS6};
DE Includes:
DE RecName: Full=RNA-directed RNA polymerase;
DE EC=2.7.7.48;
GN Name=L;
OS Crimean-Congo hemorrhagic fever virus (strain Nigeria/IbAr10200/1970)
OS (CCHFV).
OC Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina;
OC Ellioviricetes; Bunyavirales; Nairoviridae; Orthonairovirus.
OX NCBI_TaxID=652961;
OH NCBI_TaxID=9913; Bos taurus (Bovine).
OH NCBI_TaxID=9925; Capra hircus (Goat).
OH NCBI_TaxID=9606; Homo sapiens (Human).
OH NCBI_TaxID=34625; Hyalomma.
OH NCBI_TaxID=9940; Ovis aries (Sheep).
OH NCBI_TaxID=6941; Rhipicephalus microplus (Cattle tick) (Boophilus microplus).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RA Meissner J.D., Nichol S.T., StJeor S.C.;
RT "Partial sequence of CCHF virus L segment.";
RL Submitted (NOV-2003) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=15033561; DOI=10.1016/j.virol.2003.09.046;
RA Kinsella E., Martin S.G., Grolla A., Czub M., Feldmann H., Flick R.;
RT "Sequence determination of the Crimean-Congo hemorrhagic fever virus L
RT segment.";
RL Virology 321:23-28(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=15033562; DOI=10.1016/j.virol.2003.09.042;
RA Honig J.E., Osborne J.C., Nichol S.T.;
RT "Crimean-Congo hemorrhagic fever virus genome L RNA segment and encoded
RT protein.";
RL Virology 321:29-35(2004).
RN [4]
RP FUNCTION, MUTAGENESIS OF CYS-40 AND HIS-151, AND CATALYTIC ACTIVITY.
RX PubMed=18078692; DOI=10.1016/j.chom.2007.09.014;
RA Frias-Staheli N., Giannakopoulos N.V., Kikkert M., Taylor S.L., Bridgen A.,
RA Paragas J., Richt J.A., Rowland R.R., Schmaljohn C.S., Lenschow D.J.,
RA Snijder E.J., Garcia-Sastre A., Virgin H.W.;
RT "Ovarian tumor domain-containing viral proteases evade ubiquitin- and
RT ISG15-dependent innate immune responses.";
RL Cell Host Microbe 2:404-416(2007).
RN [5]
RP BIOPHYSICOCHEMICAL PROPERTIES, FUNCTION, MUTAGENESIS OF THR-10; SER-101 AND
RP GLU-128, DOMAIN, AND CATALYTIC ACTIVITY.
RX PubMed=23345508; DOI=10.1128/jvi.03252-12;
RA Capodagli G.C., Deaton M.K., Baker E.A., Lumpkin R.J., Pegan S.D.;
RT "Diversity of ubiquitin and ISG15 specificity among nairoviruses' viral
RT ovarian tumor domain proteases.";
RL J. Virol. 87:3815-3827(2013).
RN [6]
RP REVIEW.
RX PubMed=28418734; DOI=10.1080/1040841x.2017.1307805;
RA Amroun A., Priet S., de Lamballerie X., Querat G.;
RT "Bunyaviridae RdRps: structure, motifs, and RNA synthesis machinery.";
RL Crit. Rev. Microbiol. 43:753-778(2017).
RN [7]
RP FUNCTION, MUTAGENESIS OF GLN-16; CYS-40; PRO-77 AND ALA-129, AND CATALYTIC
RP ACTIVITY.
RX PubMed=28877473; DOI=10.1016/j.celrep.2017.08.040;
RA Scholte F.E.M., Zivcec M., Dzimianski J.V., Deaton M.K., Spengler J.R.,
RA Welch S.R., Nichol S.T., Pegan S.D., Spiropoulou C.F., Bergeron E.;
RT "Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses
RT via a Ubiquitin and ISG15 Specific Protease.";
RL Cell Rep. 20:2396-2407(2017).
RN [8] {ECO:0007744|PDB:3PHU, ECO:0007744|PDB:3PHW, ECO:0007744|PDB:3PHX}
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 1-183 IN COMPLEX WITH UBIQUITIN
RP AND ISG15, FUNCTION, CATALYTIC ACTIVITY, DOMAIN, ACTIVE SITE, INTERACTION
RP WITH HOST UBIQUITIN, INTERACTION WITH HOST ISG15, AND MUTAGENESIS OF GLN-16
RP AND PRO-77.
RX PubMed=21266548; DOI=10.1073/pnas.1015287108;
RA Akutsu M., Ye Y., Virdee S., Chin J.W., Komander D.;
RT "Molecular basis for ubiquitin and ISG15 cross-reactivity in viral ovarian
RT tumor domains.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:2228-2233(2011).
RN [9] {ECO:0007829|PDB:3PRM, ECO:0007829|PDB:3PRP}
RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 1-170, CATALYTIC ACTIVITY,
RP FUNCTION, ACTIVE SITE, MUTAGENESIS OF CYS-40; TRP-99; HIS-151 AND ASP-153,
RP AND INTERACTION WITH HOST UBIQUITIN.
RX PubMed=21228232; DOI=10.1128/jvi.02496-10;
RA Capodagli G.C., McKercher M.A., Baker E.A., Masters E.M., Brunzelle J.S.,
RA Pegan S.D.;
RT "Structural analysis of a viral ovarian tumor domain protease from the
RT Crimean-Congo hemorrhagic fever virus in complex with covalently bonded
RT ubiquitin.";
RL J. Virol. 85:3621-3630(2011).
RN [10] {ECO:0007829|PDB:3PSE, ECO:0007829|PDB:3PT2}
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 1-169, INTERACTION WITH HOST
RP UBIQUITIN, INTERACTION WITH HOST ISG15, AND FUNCTION.
RX PubMed=21245344; DOI=10.1073/pnas.1013388108;
RA James T.W., Frias-Staheli N., Bacik J.P., Levingston Macleod J.M.,
RA Khajehpour M., Garcia-Sastre A., Mark B.L.;
RT "Structural basis for the removal of ubiquitin and interferon-stimulated
RT gene 15 by a viral ovarian tumor domain-containing protease.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:2222-2227(2011).
RN [11] {ECO:0007744|PDB:3ZNH}
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 1-183.
RX PubMed=23387960; DOI=10.1021/ja309802n;
RA Ekkebus R., van Kasteren S.I., Kulathu Y., Scholten A., Berlin I.,
RA Geurink P.P., de Jong A., Goerdayal S., Neefjes J., Heck A.J., Komander D.,
RA Ovaa H.;
RT "On terminal alkynes that can react with active-site cysteine nucleophiles
RT in proteases.";
RL J. Am. Chem. Soc. 135:2867-2870(2013).
RN [12] {ECO:0007744|PDB:5V5G, ECO:0007744|PDB:5V5H, ECO:0007744|PDB:5V5I}
RP X-RAY CRYSTALLOGRAPHY (1.50 ANGSTROMS) OF 1-169.
RX PubMed=28542609; DOI=10.1371/journal.ppat.1006372;
RA Zhang W., Bailey-Elkin B.A., Knaap R.C.M., Khare B., Dalebout T.J.,
RA Johnson G.G., van Kasteren P.B., McLeish N.J., Gu J., He W., Kikkert M.,
RA Mark B.L., Sidhu S.S.;
RT "Potent and selective inhibition of pathogenic viruses by engineered
RT ubiquitin variants.";
RL PLoS Pathog. 13:e1006372-e1006372(2017).
CC -!- FUNCTION: Displays RNA-directed RNA polymerase, deubiquitinating and
CC deISGylase activities (PubMed:18078692, PubMed:21228232,
CC PubMed:21245344, PubMed:23345508). RNA-dependent RNA polymerase is
CC responsible for replication and transcription of the viral RNA genome
CC (PubMed:18078692). During transcription, synthesizes subgenomic RNAs
CC and assures their capping by a cap-snatching mechanism, which involves
CC the endonuclease activity cleaving the host capped pre-mRNAs (By
CC similarity). These short capped RNAs are then used as primers for viral
CC transcription (By similarity). The deubiquitinating and deISGylating
CC activities specifically cleaves poly-ubiquitinated conjugates and ISG15
CC from RIG-I, interfering with antiviral signaling pathways mediated by
CC NF-kappaB and IRF signalings (PubMed:18078692, PubMed:21266548,
CC PubMed:28877473). Deubiquitinates mono-ubiquitinated, K48- and K63-
CC linked tetra-ubiquitinated molecules (PubMed:21228232). Favors K63
CC poly-Ub linkage (PubMed:23345508). {ECO:0000250|UniProtKB:Q6GWS6,
CC ECO:0000269|PubMed:18078692, ECO:0000269|PubMed:21228232,
CC ECO:0000269|PubMed:21245344, ECO:0000269|PubMed:21266548,
CC ECO:0000269|PubMed:23345508, ECO:0000269|PubMed:28877473}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC residue protein attached to proteins as an intracellular targeting
CC signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:18078692,
CC ECO:0000269|PubMed:21228232, ECO:0000269|PubMed:23345508,
CC ECO:0000269|PubMed:28877473};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate +
CC RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:14527, Rhea:RHEA-
CC COMP:17342, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:140395;
CC EC=2.7.7.48; Evidence={ECO:0000255|PROSITE-ProRule:PRU00539};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=3.8 uM for Ub-AMC {ECO:0000269|PubMed:23345508};
CC KM=2.2 uM for ISG15-AMC {ECO:0000269|PubMed:23345508};
CC -!- SUBUNIT: Interacts (via N-terminus) with host ISG15 (via C-terminus);
CC the deISGylase activity of the viral protein interferes with antiviral
CC signaling pathways mediated by NF-kappaB and IRF signalings
CC (PubMed:21266548, PubMed:21245344). Interacts with host ubiquitin
CC (PubMed:21245344). {ECO:0000269|PubMed:21245344,
CC ECO:0000269|PubMed:21266548}.
CC -!- INTERACTION:
CC Q6TQR6; P05161: ISG15; Xeno; NbExp=5; IntAct=EBI-4403908, EBI-746466;
CC -!- DOMAIN: The viral OTU domain (vOTU) and its N-terminal extension is
CC responsible for ubiquitin and ISG15 binding and for the
CC deubiquitination and deISGylation activities.
CC {ECO:0000269|PubMed:21266548, ECO:0000269|PubMed:23345508}.
CC -!- MISCELLANEOUS: Classified as His(+) endonuclease since it has a
CC histidine upstream of the active site that coordinates the first
CC cation. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the Bunyavirales RNA polymerase family.
CC {ECO:0000305}.
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DR EMBL; AY422209; AAQ98866.2; -; Genomic_RNA.
DR EMBL; AY389361; AAR25663.2; -; Genomic_RNA.
DR EMBL; AY389508; AAQ90157.2; -; Genomic_RNA.
DR PDB; 3PHU; X-ray; 2.20 A; A/B=1-217.
DR PDB; 3PHW; X-ray; 2.00 A; A/C/E/G=1-183.
DR PDB; 3PHX; X-ray; 1.60 A; A=1-183.
DR PDB; 3PRM; X-ray; 2.30 A; A/C=1-170.
DR PDB; 3PRP; X-ray; 1.70 A; A/C=1-170.
DR PDB; 3PSE; X-ray; 2.30 A; A=1-169.
DR PDB; 3PT2; X-ray; 2.50 A; A=1-184.
DR PDB; 3ZNH; X-ray; 2.30 A; A=1-183.
DR PDB; 5V5G; X-ray; 2.10 A; A/C=1-183.
DR PDB; 5V5H; X-ray; 1.50 A; A=1-169.
DR PDB; 5V5I; X-ray; 2.20 A; A/C=1-169.
DR PDBsum; 3PHU; -.
DR PDBsum; 3PHW; -.
DR PDBsum; 3PHX; -.
DR PDBsum; 3PRM; -.
DR PDBsum; 3PRP; -.
DR PDBsum; 3PSE; -.
DR PDBsum; 3PT2; -.
DR PDBsum; 3ZNH; -.
DR PDBsum; 5V5G; -.
DR PDBsum; 5V5H; -.
DR PDBsum; 5V5I; -.
DR SMR; Q6TQR6; -.
DR DIP; DIP-60307N; -.
DR IntAct; Q6TQR6; 1.
DR MEROPS; C87.001; -.
DR PRIDE; Q6TQR6; -.
DR EvolutionaryTrace; Q6TQR6; -.
DR PRO; PR:Q6TQR6; -.
DR Proteomes; UP000008767; Genome.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IEA:UniProtKB-EC.
DR GO; GO:0000166; F:nucleotide binding; IEA:UniProtKB-KW.
DR GO; GO:0003968; F:RNA-directed 5'-3' RNA polymerase activity; IEA:UniProtKB-KW.
DR GO; GO:0039648; P:modulation by virus of host protein ubiquitination; IEA:UniProtKB-KW.
DR GO; GO:0039689; P:negative stranded viral RNA replication; ISS:UniProtKB.
DR GO; GO:0039696; P:RNA-templated viral transcription; ISS:UniProtKB.
DR GO; GO:0039579; P:suppression by virus of host ISG15-protein conjugation; IEA:UniProtKB-KW.
DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0006351; P:transcription, DNA-templated; IEA:InterPro.
DR InterPro; IPR003323; OTU_dom.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR015843; RNA-dir_pol_nairovirus.
DR InterPro; IPR007099; RNA-dir_pol_NSvirus.
DR InterPro; IPR007322; RNA_pol_bunyavir.
DR Pfam; PF04196; Bunya_RdRp; 1.
DR Pfam; PF02338; OTU; 1.
DR PIRSF; PIRSF036900; RdRPol_NRV; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
DR PROSITE; PS50802; OTU; 1.
DR PROSITE; PS50525; RDRP_SSRNA_NEG_SEG; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Host-virus interaction; Hydrolase;
KW Inhibition of host innate immune response by virus;
KW Inhibition of host interferon signaling pathway by virus;
KW Inhibition of host ISG15 by virus; Magnesium; Manganese; Metal-binding;
KW Modulation of host ubiquitin pathway by viral deubiquitinase;
KW Modulation of host ubiquitin pathway by virus; Nucleotide-binding;
KW Nucleotidyltransferase; Reference proteome; RNA-directed RNA polymerase;
KW Transferase; Viral immunoevasion; Viral RNA replication.
FT CHAIN 1..3945
FT /note="RNA-directed RNA polymerase L"
FT /id="PRO_0000396080"
FT DOMAIN 29..158
FT /note="OTU"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00139"
FT DOMAIN 2342..2551
FT /note="RdRp catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00539"
FT REGION 1..28
FT /note="Essential for the vOTU enzymatic activity"
FT /evidence="ECO:0000269|PubMed:21266548"
FT REGION 625..806
FT /note="Endonuclease"
FT /evidence="ECO:0000250|UniProtKB:Q66431"
FT REGION 763..790
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2712..2744
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 776..790
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 40
FT /note="For ubiquitin thioesterase activity"
FT /evidence="ECO:0000269|PubMed:21228232,
FT ECO:0000269|PubMed:21266548"
FT ACT_SITE 151
FT /note="For ubiquitin thioesterase activity"
FT /evidence="ECO:0000269|PubMed:21228232,
FT ECO:0000269|PubMed:21266548, ECO:0000305|PubMed:18078692"
FT ACT_SITE 153
FT /note="For ubiquitin thioesterase activity"
FT /evidence="ECO:0000269|PubMed:21228232,
FT ECO:0000269|PubMed:21266548"
FT ACT_SITE 734
FT /note="For endonuclease activity"
FT /evidence="ECO:0000250|UniProtKB:I0DF35"
FT BINDING 632
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q6GWS6"
FT BINDING 693
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q6GWS6"
FT BINDING 693
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q6GWS6"
FT BINDING 718
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q66431"
FT BINDING 2518
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="catalytic; for RdRp activity"
FT /evidence="ECO:0000250|UniProtKB:I0DF35"
FT MUTAGEN 10
FT /note="T->E: Increase of 50% in debubiquitination
FT activity."
FT /evidence="ECO:0000269|PubMed:23345508"
FT MUTAGEN 16
FT /note="Q->R: Complete loss of debubiquitination activity.
FT No effect on deISGylation. Unable to block RIG-I-mediated
FT gene activation."
FT /evidence="ECO:0000269|PubMed:21266548,
FT ECO:0000269|PubMed:28877473"
FT MUTAGEN 40
FT /note="C->A: Almost complete loss of OTU proteolytic
FT activity. Unable to block RIG-I-mediated gene activation."
FT /evidence="ECO:0000269|PubMed:21228232,
FT ECO:0000269|PubMed:21266548, ECO:0000269|PubMed:28877473"
FT MUTAGEN 40
FT /note="C->A: Loss of deubiquitinating and deISGylase
FT activities."
FT /evidence="ECO:0000269|PubMed:18078692"
FT MUTAGEN 77
FT /note="P->D: Complete loss of deISGylation and
FT debubiquitination activities."
FT /evidence="ECO:0000269|PubMed:21266548,
FT ECO:0000269|PubMed:28877473"
FT MUTAGEN 99
FT /note="W->A: Almost complete loss of OTU proteolytic
FT activity."
FT MUTAGEN 101
FT /note="S->G: More than 60% loss of deISGylation and
FT debubiquitination activities."
FT /evidence="ECO:0000269|PubMed:23345508"
FT MUTAGEN 128
FT /note="E->T: Loss of 40% activity for debubiquitination and
FT 75% for deISGylation activity."
FT /evidence="ECO:0000269|PubMed:23345508"
FT MUTAGEN 129
FT /note="A->R: Complete loss of deISGylation and
FT debubiquitination activities. Unable to block RIG-I-
FT mediated gene activation."
FT /evidence="ECO:0000269|PubMed:28877473"
FT MUTAGEN 151
FT /note="H->A: 350-fold loss of proteolytic activity."
FT /evidence="ECO:0000269|PubMed:21228232"
FT MUTAGEN 151
FT /note="H->A: Loss of deubiquitinating and deISGylase
FT activities; when associated with Ala-40."
FT /evidence="ECO:0000269|PubMed:18078692"
FT MUTAGEN 153
FT /note="D->A: 40-fold loss of proteolytic activity."
FT /evidence="ECO:0000269|PubMed:21228232"
FT CONFLICT 1047
FT /note="E -> G (in Ref. 2; AAR25663)"
FT /evidence="ECO:0000305"
FT CONFLICT 1660
FT /note="T -> P (in Ref. 2; AAR25663)"
FT /evidence="ECO:0000305"
FT CONFLICT 1675
FT /note="N -> T (in Ref. 2; AAR25663)"
FT /evidence="ECO:0000305"
FT CONFLICT 2675..2678
FT /note="VSSA -> ASST (in Ref. 1; AAQ98866)"
FT /evidence="ECO:0000305"
FT HELIX 3..6
FT /evidence="ECO:0007829|PDB:5V5H"
FT STRAND 10..13
FT /evidence="ECO:0007829|PDB:5V5H"
FT STRAND 16..19
FT /evidence="ECO:0007829|PDB:5V5H"
FT HELIX 25..28
FT /evidence="ECO:0007829|PDB:5V5H"
FT STRAND 29..32
FT /evidence="ECO:0007829|PDB:5V5H"
FT STRAND 36..38
FT /evidence="ECO:0007829|PDB:5V5G"
FT HELIX 40..49
FT /evidence="ECO:0007829|PDB:5V5H"
FT STRAND 50..52
FT /evidence="ECO:0007829|PDB:5V5I"
FT TURN 55..57
FT /evidence="ECO:0007829|PDB:5V5H"
FT HELIX 58..72
FT /evidence="ECO:0007829|PDB:5V5H"
FT HELIX 73..75
FT /evidence="ECO:0007829|PDB:5V5H"
FT HELIX 79..82
FT /evidence="ECO:0007829|PDB:5V5H"
FT HELIX 86..93
FT /evidence="ECO:0007829|PDB:5V5H"
FT HELIX 102..112
FT /evidence="ECO:0007829|PDB:5V5H"
FT STRAND 116..135
FT /evidence="ECO:0007829|PDB:5V5H"
FT TURN 138..140
FT /evidence="ECO:0007829|PDB:5V5H"
FT STRAND 141..147
FT /evidence="ECO:0007829|PDB:5V5H"
FT TURN 148..150
FT /evidence="ECO:0007829|PDB:5V5H"
FT STRAND 151..157
FT /evidence="ECO:0007829|PDB:5V5H"
FT HELIX 159..161
FT /evidence="ECO:0007829|PDB:5V5H"
FT HELIX 171..182
FT /evidence="ECO:0007829|PDB:3PHU"
SQ SEQUENCE 3945 AA; 447940 MW; 04509FFA1C33805F CRC64;
MDFLRSLDWT QVIAGQYVSN PRFNISDYFE IVRQPGDGNC FYHSIAELTM PNKTDHSYHY
IKRLTESAAR KYYQEEPEAR LVGLSLEDYL KRMLSDNEWG STLEASMLAK EMGITIIIWT
VAASDEVEAG IKFGDGDVFT AVNLLHSGQT HFDALRILPQ FETDTREALS LMDRVIAVDQ
LTSSSSDELQ DYEDLALALT SAEESNRRSS LDEVTLSKKQ AEILRQKASQ LSKLVNKSQN
IPTRVGRVLD CMFNCKLCVE ISADTLILRP ESKEKIGEIM SLRQLGHKLL TRDKQIKQEF
SRMKLYVTKD LLDHLDVGGL LRAAFPGTGI ERHMQLLHSE MILDICTVSL GVMLSTFLYG
SNNKNKKKFI TNCLLSTALS GKKVYKVLGN LGNELLYKAP RKALATVCSA LFGKQINKLQ
NCFRTISPVS LLALRNLDFD CLSVQDYNGM IENMSKLDNT DVEFNHREIA DLNQLTSRLI
TLRKEKDTDL LKQWFPESDL TRRSIRNAAN AEEFVISEFF KKKDIMKFIS TSGRAMSAGK
IGNVLSYAHN LYLSKSSLNM TSEDISQLLI EIKRLYALQE DSEVEPIAII CDGIESNMKQ
LFAILPPDCA RECEVLFDDI RNSPTHSTAW KHALRLKGTA YEGLFANCYG WQYIPEDIKP
SLTMLIQTLF PDKFEDFLDR TQLHPEFRDL TPDFSLTQKV HFKRNQIPSV ENVQISIDAT
LPESVEAVPV TERKMFPLPE TPLSEVHSIE RIMENFTRLM HGGRLSTKKR DGDPAEQGNQ
QSITEHESSS ISAFKDYGER GIVEENHMKF SGEDQLETRQ LLLVEVGFQT DIDGKIRTDH
KKWKDILKLL ELLGIKCSFI ACADCSSTPP DRWWITEDRV RVLKNSVSFL FNKLSRNSPT
EVTDIVVGAI STQKVRSYLK AGTATKTPVS TKDVLETWEK MKEHILNRPT GLTLPTSLEQ
AMRKGLVEGV VISKEGSESC INMLKENLDR ITDEFERTKF KHELTQNITT SEKMLLSWLS
EDIKSSRCGE CLSNIKKAVD ETANLSEKIE LLAYNLQLTN HCSNCHPNGV NISNTSNVCK
RCPKIEVVSH CENKGFEDSN ECLTDLDRLV RLTLPGKTEK ERRVKRNVEY LIKLMMSMSG
IDCIKYPTGQ LITHGRVSAK HNDGNLKDRS DDDQRLAEKI DTVRKELSES KLKDYSTYAR
GVISNSLKNL SRQGKSKCSV PRSWLEKVLF DLKVPTKDEE VLINIRNSLK ARSEFVRNND
KLLIRSKEEL KKCFDVQSFK LKKNKQPVPF QVDCILFKEV AAECMKRYIG TPYEGIVDTL
VSLINVLTRF TWFQEVVLYG KICETFLRCC TEFNRSGVKL VKIRHCNINL SVKLPSNKKE
NMLCCLYSGN MELLQGPFYL NRRQAVLGSS YLYIVITLYI QVLQQYRCLE VINSVSEKTL
QDIENHSMTL LEDSFREITF ALEGRFEESY KIRTSRCRAS GNFLNRSSRD HFISVVSGLN
LVYGFLIKDN LLANSQQQNK QLQMLRFGML AGLSRLVCPN ELGKKFSTSC RRIEDNIARL
YLQTSIYCSV RDVEDNVKHW KQRDLCPEVT IPCFTVYGTF VNSDRQLIFD IYNVHIYNKE
MDNFDEGCIS VLEETAERHM LWELDLMNSL CSDEKKDTRT ARLLLGCPNV RKAANREGKK
LLKLNSDTST DTQSIASEVS DRRSYSSSKS RIRSIFGRYN SQKKPFELRS GLEVFNDPFN
DYQQAITDIC QFSEYTPNKE SILKDCLQII RKNPSHTMGS FELIQAISEF GMSKFPPENI
DKARRDPKNW VSISEVTETT SIVASPRTHM MLKDCFKIIL GTENKKIVKM LRGKLKKLGA
ISTNIEIGKR DCLDLLSTVD GLTDQQKENI VNGIFEPSKL SFYHWKELVK KNIDEVLLTE
DGNLIFCWLK TISSSVKGSL KKRLKFMNIH SPELMPENCL FSSEEFNELI KLKKLLLNEQ
QDEQELKQDL LISSWIKCIT ACKDFASIND KIQKFIYHLS EELYDIRLQH LELSKLKQEH
PSVSFTKEEV LIKRLEKNFL KQHNLEIMET VNLVFFAALS APWCLHYKAL ESYLVRHPEI
LDCGSKEDCK LTLLDLSVSK LLVCLYQKDD EELINSSSLK LGFLVKYVVT LFTSNGEPFS
LSLNDGGLDL DLHKTTDEKL LHQTKIVFAK IGLSGNSYDF IWTTQMIANS NFNVCKRLTG
RSTGERLPRS VRSKVIYEMV KLVGETGMAI LQQLAFAQAL NYEHRFYAVL APKAQLGGAR
DLLVQETGTK VMHATTEMFS RNLLKTTSDD GLTNPHLKET ILNVGLDCLA NMRNLDGKPI
SEGSNLVNFY KVICISGDNT KWGPIHCCSF FSGMMQQVLK NVPDWCSFYK LTFIKNLCRQ
VEIPAGSIKK ILNVLRYRLC SKGGVEQHSE EDLRRLLTDN LDSWDGNDTV KFLVTTYISK
GLMALNSYNH MGQGIHHATS SVLTSLAAVL FEELAIFYLK RSLPQTTVHV EHAGSSDDYA
KCIVVTGILS KELYSQYDET FWKHACRLKN FTAAVQRCCQ MKDSAKTLVS DCFLEFYSEF
MMGYRVTPAV IKFMFTGLIN SSVTSPQSLM QACQVSSQQA MYNSVPLVTN TAFTLLRQQI
FFNHVEDFIR RYGILTLGTL SPFGRLFVPT YSGLVSSAVA LEDAEVIARA AQTLQMNSVS
IQSSSLTTLD SLGRSRTSST AEDSSSVSDT TAASHDSGSS SSSFSFELNR PLSETELQFI
KALSSLKSTQ ACEVIQNRIT GLYCNSNEGP LDRHNVIYSS RMADSCDWLK DGKRRGNLEL
ANRIQSVLCI LIAGYYRSFG GEGTEKQVKA SLNRDDNKII EDPMIQLIPE KLRRELERLG
VSRMEVDELM PSISPDDTLA QLVAKKLISL NVSTEEYSAE VSRLKQTLTA RNVLHGLAGG
IKELSLPIYT IFMKSYFFKD NVFLSLTDRW STKHSTNYRD SCGKQLKGRI ITKYTHWLDT
FLGCSVSINR HTTVKEPSLF NPNIRCVNLI TFEDGLRELS VIQSHLKVFE NEFTNLNLQF
SDPNRQKLRI VESRPAESEL EANRAVIVKT KLFSATEQVR LSNNPAVVMG YLLDESAISE
VKPTKVDFSN LLKDRFKIMQ FFPSVFTLIK MLTDESSDSE KSGLSPDLQQ VARYSNHLTL
LSRMIQQAKP TVTVFYMLKG NLMNTEPTVA ELVSYGIKEG RFFRLSDTGV DASTYSVKYW
KILHCISAIG CLPLSQADKS SLLMSFLNWR VNMDIRTSDC PLSSHEASIL SEFDGQVIAN
ILASELSSVK RDSEREGLTD LLDYLNSPTE LLKKKPYLGT TCKFNTWGDS NRSGKFTYSS
RSGESIGIFI AGKLHIHLSS ESVALLCETE RQVLSWMSKR RTEVITKEQH QLFLSLLPQS
HECLQKHKDG SALSVIPDSS NPRLLKFVPL KKGLAVVKIK KQILTVKKQV VFDAESEPRL
QWGHGCLSIV YDETDTQTTY HENLLKVKHL VDCSTDRKKL LPQSVFSDSK VVLSRIKFKT
ELLLNSLTLL HCFLKHAPSD AIMEVESKSS LLHKYLKSGG VRQRNTEVLF REKLNKVVIK
DNLEQGVEEE IEFCNNLTKT VSENPLPLSC WSEVQNYIED IGFNNVLVNI DRNTVKSELL
WKFTLDTNVS TTSTIKDVRT LVSYVSTETI PKFLLAFLLY EEVLMNLINQ CKAVKELINS
TGLSDLELES LLTLCAFYFQ SECSKRDGPR CSFAALLSLI HEDWQRIGKN ILVRANNELG
DVSLKVNIVL VPLKDMSKPK SERVVMARRS LNHALSLMFL DEMSLPELKS LSVNCKMGNF
EGQECFEFTI LKDNSARLDY NKLIDHCVDM EKKREAVRAV EDLILMLTGR AVKPSAVTQF
VHGDEQCQEQ ISLDDLMAND TVTDFPDREA EALKTGNLGF NWDSD
