VKT2H_HETCR
ID VKT2H_HETCR Reviewed; 56 AA.
AC P0DL86; A0A3G1GLI4;
DT 31-JAN-2018, integrated into UniProtKB/Swiss-Prot.
DT 31-JAN-2018, sequence version 1.
DT 25-MAY-2022, entry version 9.
DE RecName: Full=PI-stichotoxin-Hcr2h {ECO:0000305};
DE Short=PI-SHTX-Hcr2h {ECO:0000305};
DE AltName: Full=Kunitz-type serine protease inhibitor HCRG21 {ECO:0000303|PubMed:27983679};
OS Heteractis crispa (Leathery sea anemone) (Radianthus macrodactylus).
OC Eukaryota; Metazoa; Cnidaria; Anthozoa; Hexacorallia; Actiniaria;
OC Stichodactylidae; Heteractis.
OX NCBI_TaxID=175771;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND 3D-STRUCTURE MODELING.
RX PubMed=27983679; DOI=10.3390/md14120229;
RA Monastyrnaya M., Peigneur S., Zelepuga E., Sintsova O., Gladkikh I.,
RA Leychenko E., Isaeva M., Tytgat J., Kozlovskaya E.;
RT "Kunitz-type peptide HCRG21 from the sea anemone Heteractis crispa is a
RT full antagonist of the TRPV1 receptor.";
RL Mar. Drugs 14:1-20(2016).
RN [2]
RP MUTAGENESIS OF SER-5.
RX PubMed=33158163; DOI=10.3390/biomedicines8110473;
RA Gladkikh I., Peigneur S., Sintsova O., Lopes Pinheiro-Junior E.,
RA Klimovich A., Menshov A., Kalinovsky A., Isaeva M., Monastyrnaya M.,
RA Kozlovskaya E., Tytgat J., Leychenko E.;
RT "Kunitz-type peptides from the sea anemone Heteractis crispa demonstrate
RT potassium channel blocking and anti-inflammatory activities.";
RL Biomedicines 8:0-0(2020).
RN [3]
RP FUNCTION, AND RECOMBINANT EXPRESSION.
RX PubMed=33802055; DOI=10.3390/biomedicines9030283;
RA Sintsova O., Gladkikh I., Monastyrnaya M., Tabakmakher V., Yurchenko E.,
RA Menchinskaya E., Pislyagin E., Andreev Y., Kozlov S., Peigneur S.,
RA Tytgat J., Aminin D., Kozlovskaya E., Leychenko E.;
RT "Sea anemone kunitz-type peptides demonstrate neuroprotective activity in
RT the 6-hydroxydopamine induced neurotoxicity model.";
RL Biomedicines 9:0-0(2021).
CC -!- FUNCTION: This protease inhibitor shows two different activities.
CC Almost completely (95%) inhibits TRPV1 (IC(50)=6.9 uM), the capsaicin
CC receptor, a non-selective cation channel expressed by sensory neurons
CC of the pain pathway (PubMed:27983679). The toxin also shows a weak
CC inhibition of trypsin and chymotrypsin activity (Ki=0.2 uM and Ki=0.7
CC uM, respectively) (PubMed:27983679). Shows analgesic effect on mammals
CC (By similarity). In vitro, it shows cytoprotective activity in the
CC oxidative stress agent 6-hydroxydopamine (6-OHDA)-induced neurotoxicity
CC model (PubMed:33802055). In this model, it decreases reactive oxygen
CC species (ROS) levels, and increases cell viability in a correlated
CC manner (PubMed:33802055). It is possible that the observed effect is
CC due to the ability of this peptides to act as free-radical scavenger
CC (PubMed:33802055). The neuroprotective effect could also be indirect
CC evidence of TRPV1 involvement in the disorders associated with
CC neurodegeneration (PubMed:33802055). {ECO:0000250|UniProtKB:B2G331,
CC ECO:0000269|PubMed:27983679}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:B2G331}.
CC Nematocyst {ECO:0000250|UniProtKB:B2G331}.
CC -!- MISCELLANEOUS: Does not inhibit Kv1.1/KCNA1, Kv1.2/KCNA2, Kv1.3/KCNA3,
CC Kv1.4/KCNA4, Kv1.5/KCNA5, Kv1.6/KCNA6, shaker IR and hErg/Kv11.1/KCNH2
CC potassium channels. {ECO:0000269|PubMed:27983679}.
CC -!- SIMILARITY: Belongs to the venom Kunitz-type family. Sea anemone type 2
CC potassium channel toxin subfamily. {ECO:0000305}.
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DR EMBL; KX900498; APQ42938.1; -; mRNA.
DR AlphaFoldDB; P0DL86; -.
DR SMR; P0DL86; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0042151; C:nematocyst; IEA:UniProtKB-SubCell.
DR GO; GO:0099106; F:ion channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR CDD; cd00109; KU; 1.
DR Gene3D; 4.10.410.10; -; 1.
DR InterPro; IPR002223; Kunitz_BPTI.
DR InterPro; IPR036880; Kunitz_BPTI_sf.
DR InterPro; IPR020901; Prtase_inh_Kunz-CS.
DR Pfam; PF00014; Kunitz_BPTI; 1.
DR PRINTS; PR00759; BASICPTASE.
DR SMART; SM00131; KU; 1.
DR SUPFAM; SSF57362; SSF57362; 1.
DR PROSITE; PS00280; BPTI_KUNITZ_1; 1.
DR PROSITE; PS50279; BPTI_KUNITZ_2; 1.
PE 1: Evidence at protein level;
KW Disulfide bond; Ion channel impairing toxin; Nematocyst;
KW Protease inhibitor; Secreted; Serine protease inhibitor; Toxin.
FT CHAIN 1..56
FT /note="PI-stichotoxin-Hcr2h"
FT /evidence="ECO:0000305|PubMed:27983679"
FT /id="PRO_0000442800"
FT DOMAIN 4..54
FT /note="BPTI/Kunitz inhibitor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT SITE 14..15
FT /note="Reactive bond for trypsin"
FT /evidence="ECO:0000250|UniProtKB:P31713"
FT DISULFID 4..54
FT /evidence="ECO:0000250|UniProtKB:P31713"
FT DISULFID 13..37
FT /evidence="ECO:0000250|UniProtKB:P31713"
FT DISULFID 29..50
FT /evidence="ECO:0000250|UniProtKB:P31713"
FT MUTAGEN 5
FT /note="S->L: Very weak gain of function on Kv1.1/KCNA1
FT (IC(50)=15.6 uM), Kv1.2/KCNA2, and Kv1.3/KCNA3 potassium
FT channels."
FT /evidence="ECO:0000269|PubMed:33158163"
SQ SEQUENCE 56 AA; 6234 MW; 613B54812C4192B0 CRC64;
RGICSEPKVV GPCTAYFRRF YFDSETGKCT PFIYGGCEGN GNNFETLRAC RAICRA
