SIIIA (P02707) Protein Card

General Information
Name SIIIA
Alternative name(s) S3-RDHAR04
Organism Conus striatus (Striated cone)
Organism region Indo-Pacific
Organism diet piscivorous
Protein Type Wild type
Protein precursor SIIIA precursor (825)
SIIIA precursor (4905)
Notes The experimental evidence of the presence of this peptide in the venom come from Schroeder et al. 2008. Block tetrodotoxin resistant (TTX-R) and sensitive (TTX-S) Na channels (Bulaj et al 2005). Presumably interacts with site 1 in the Na channel pore, because SIIIA competes with TIIIA (Schroeder et al 2008), which in turn competes with saxitoxin (Lewis et al 2007). 10 μM rapidly blocks A-fiber compound action potentials in mouse sciatic nerve. Slowly blocks C-fiber CAPs [Wilson,M.J., Zhang,M (2015)].

Classification
Conopeptide class conotoxin
Gene superfamily M superfamily
Cysteine framework III
Pharmacological family mu conotoxin

Sequence
ZNCCNGGCSSKWCRDHARCC(nh2)
Modified residues
positionsymbolname
1ZPyroglutamic acid
21nh2C-term amidation
Sequence evidence protein level
Average Mass NA
Monoisotopic Mass NA
Isoelectric Point 11.62
Extinction Coefficient [280nm] 5500.00

Activity

IC50: Voltage-Gated Sodium Channels

TargetOrganismIC50Ref
Nav1.1R. norvegicus11.0uM+/-1.2Yao,S. et al. (2008)
Nav1.2R. norvegicus790nMSchroeder,C.I. et al. (2008)
Nav1.3R. norvegicus5.3uMSchroeder,C.I. et al. (2008)
11.0uM+/-1.4Yao,S. et al. (2008)
Nav1.4R. norvegicus0.56uM+/-0.29Leipold,E. et al. (2011)
330nMSchroeder,C.I. et al. (2008)
130nM+/-15Yao,S. et al. (2008)
Nav1.5R. norvegicus251uM+/-38Yao,S. et al. (2008)
Nav1.6M. musculus760nM+/-60Yao,S. et al. (2008)
Nav1.7R. norvegicus65uM+/-6Yao,S. et al. (2008)
Nav1.8R. norvegicus>10uMWilson,M.J. et al. (2011)

Kd: Voltage-Gated Sodium Channels

TargetOrganismKdRef
Nav1.2R. norvegicus50nM+/-17Wilson,M.J. et al. (2011)

Ki: Voltage-Gated Sodium Channels

TargetOrganismKiCompetitorAgonistRef
Nav1.2R. norvegicus(Measured in rat brain preparation.)9.55 nM125I-TIIIASchroeder,C.I. et al. (2008)
Nav1.4R. norvegicus(Measured in rat muscle preparation.)21.38 nM125I-TIIIASchroeder,C.I. et al. (2008)

Percentage inhibition: Voltage-Gated Potassium Channels

TargetOrganism% inhibitionConcentrationRef
Kv1.1R. norvegicus27.3+/-3.710 uMLeipold,E. et al. (2017)
Kv1.2R. norvegicus410 uMLeipold,E. et al. (2017)
Kv1.3R. norvegicus1210 uMLeipold,E. et al. (2017)
Kv1.4R. norvegicus1210 uMLeipold,E. et al. (2017)
Kv1.5R. norvegicus310 uMLeipold,E. et al. (2017)
Kv1.6R. norvegicus54.0+/-1.310 uMLeipold,E. et al. (2017)
Kv2.1R. norvegicus210 uMLeipold,E. et al. (2017)

Percentage inhibition: Voltage-Gated Sodium Channels

TargetOrganism% inhibitionConcentrationRef
Nav1.2R. norvegicus953uMSchroeder,C.I. et al. (2008)
9510 uMLeipold,E. et al. (2017)
Nav1.3R. norvegicus453uMSchroeder,C.I. et al. (2008)
Nav1.4R. norvegicus89+/-2100uMLeipold,E. et al. (2011)
8510 uMLeipold,E. et al. (2017)
Nav1.5H. sapiens12+/-10100uMLeipold,E. et al. (2011)
16+/-210uMLeipold,E. et al. (2011)
R. norvegicus2010 uMLeipold,E. et al. (2017)
03uMSchroeder,C.I. et al. (2008)
Nav1.7R. norvegicus7010 uMLeipold,E. et al. (2017)
03uMSchroeder,C.I. et al. (2008)
Nav1.8R. norvegicus03uMSchroeder,C.I. et al. (2008)
Nav TTX-RR. norvegicus1001uMWang,C.Z. et al. (2006)
R. pipiens91+/-85uMZhang,M.M. et al. (2006)
Nav TTX-SR. norvegicus0500nMWang,C.Z. et al. (2006)

Synthetic variants
SIIIA[C3U,C13U] ZNUCNGGCSSKWURDHARCC(nh2)
SIIIA[C4U,C19U]ZNCUNGGCSSKWCRDHARUC(nh2)
SIIIA[C8U,C20U]ZNCCNGGUSSKWCRDHARCU(nh2)
SIIIA[del1,D15A,H16D]NCCNGGCSSKWCRADARCC(nh2)
SIIIA[del1,D15A,H16R]NCCNGGCSSKACRARARCC(nh2)
SIIIA[del1,D15A,H16Y]NCCNGGCSSKWCRAYARCC(nh2)
SIIIA[del1,D15A,insC_AA]NCCNGGCSSKWCRAHARCCAA(nh2)
SIIIA[del1,D15A,insC_AD]NCCNGGCSSKWCRAHARCCAD(nh2)
SIIIA[del1,D15A,insC_AK]NCCNGGCSSKWCRAHARCCAK(nh2)
SIIIA[del1,D15A,insC_A]NCCNGGCSSKWCRAHARCCA(nh2)
SIIIA[del1,D15A,insC_D]NCCNGGCSSKWCRAHARCCD(nh2)
SIIIA[del1,D15A,insC_K]NCCNGGCSSKWCRAHARCCK(nh2)
SIIIA[del1,D15A]NCCNGGCSSKWCRAHARCC(nh2)
SIIIA[del1,D15K]NCCNGGCSSKWCRKHARCC(nh2)
SIIIA[del1,H16A]NCCNGGCSSKWCRDAARCC(nh2)
SIIIA[del1,K11A,R14A,D15A,H16D,R18A]NCCNGGCSSAWCAADAACC(nh2)
SIIIA[del1,K11A,R14A,D15A,H16Y,R18A]NCCNGGCSSAWCAAYAACC(nh2)
SIIIA[del1,K11A,R14A,D15A,R18A]NCCNGGCSSAWCAAHAACC(nh2)
SIIIA[del1,K11A]NCCNGGCSSAWCRDHARCC(nh2)
SIIIA[del1,K11R,W12A,D15A]NCCNGGCSSRACRAHARCC(nh2)
SIIIA[del1,K11R,W12A]NCCNGGCSSRACRDHARCC(nh2)
SIIIA[del1,R14A]NCCNGGCSSKWCADHARCC(nh2)
SIIIA[del1,R18A]NCCNGGCSSKWCRDHAACC(nh2)
SIIIA[del1,W12A]NCCNGGCSSKACRDHARCC(nh2)
SIIIA[del1]NCCNGGCSSKWCRDHARCC(nh2)

References
Wang,C.Z., Zhang,H., Jiang,H., Lu,W., Zhao,Z.Q. and Chi,C.W. (2006) A novel conotoxin from Conus striatus, mu-SIIIA, selectively blocking rat tetrodotoxin-resistant sodium channels Toxicon 47:122-132
Bulaj,G., West,P.J., Garrett,J.E., Watkins,M., Zhang,M.M., Norton,R.S., Smith,B.J., Yoshikami,D. and Olivera,B.M. (2005) Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels Biochemistry 44:7259-7265
Schroeder,C.I., Ekberg,J., Nielsen,K.J., Adams,D., Loughnan,M.L., Thomas,L., Adams,D.J., Alewood,P.F. and Lewis,R.J. (2008) Neuronally mu-conotoxins from Conus striatus utilize an alpha-helical motif to target mammalian sodium channels. J. Biol. Chem. 283:21621-21628
Yao,S., Zhang,M.M., Yoshikami,D., Azam,L., Olivera,B.M., Bulaj,G. and Norton,R.S. (2008) Structure, dynamics, and selectivity of the sodium channel blocker mu-conotoxin SIIIA. Biochemistry 47:10940-10949
Leipold,E., Markgraf,R., Miloslavina,A., Kijas,M., Schirmeyer,J. , Imhof,D., and Heinemann,S.H (2011) Molecular determinants for the subtype specificity of μ-conotoxin SIIIA targeting neuronal voltage-gated sodium channels. Neuropharmacology 61:105-111
Schroeder,C.I., Adams,D., Thomas,L., Alewood,P.F. and Lewis,R.J. (2012) N- and C-terminal extensions of μ-conotoxins increase potency and selectivity for neuronal sodium channels. Biopolymers 98:161-165
Wilson,M.J., Zhang,M.M., Gajewiak,J., Azam,L., Rivier,J.E., Olivera,B.M. and Yoshikami,D. (2015) Α- and β-subunit composition of voltage-gated sodium channels investigated with μ-conotoxins and the recently discovered μO§-conotoxin GVIIJ. J. Neurophysiol. 113:2289-2301
Leipold,E., Ullrich,F., Thiele,M., Tietze,A.A., Terlau,H., Imhof,D. and Heinemann,S.H. (2017) Subtype-specific block of voltage-gated K+ channels by μ-conopeptides Biochem. Biophys. Res. Commun. 482:1135-1140
Paul George,A.A., Heimer,P., Maaß,A., Hamaekers,J., Hofmann-Apitius,M., Biswas,A. and Imhof,D. (2018) Insights into the Folding of Disulfide-Rich μ-Conotoxins ACS Omega 3:12330-12340

Internal links
Protein Precursor SIIIA precursor (825)
SIIIA precursor (4905)
Nucleic acids
Structure Structure, dynamics and selectivity of the sodium channel blocker mu-conotoxin SIIIA
NMR solution structure of mu-conotoxin SIIIA

External links
Ncbi AAO48588, Q86DU6

Tools