Reviewed, UniProtKB/Swiss-Prot P56636 (CXA2_CONMA)

Names and origin

Protein names	Recommended name:     Alpha-conotoxin MII       Short name=CtxMII       Short name=Alpha-MII Alternative name(s):     Alpha-conotoxin M2
Organism	Conus magus (Magus cone) (Magician's cone snail)
Taxonomic identifier	6492 [NCBI]
Taxonomic lineage	Eukaryota › Metazoa › Mollusca › Gastropoda › Orthogastropoda › Apogastropoda › Caenogastropoda › Sorbeoconcha › Hypsogastropoda › Neogastropoda › Conoidea › Conidae › Conus

Protein attributes

Sequence length	68 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Alpha-conotoxins bind to the nicotinic acetylcholine receptors (nAChR) and inhibit them. This toxin blocks neuronal mammalian nAChRs (alpha-6 or -3/beta-2 or -3 > alpha-3/beta-2 > alpha-3/beta-4 = alpha-4/beta-2).
Subcellular location	Secreted.
Tissue specificity	Expressed by the venom duct.
Miscellaneous	There are currently a number of patents describing the use of this peptide in therapeutic applications.
Sequence similarities	Belongs to the conotoxin A superfamily. Alpha-type family.
Mass spectrometry	Molecular weight is 1710.6 Da from positions 49 - 64. Determined by LSI. Ref.3

Ontologies

Keywords
Cellular component	Secreted
Domain	Signal
Molecular function	Acetylcholine receptor inhibitor Neurotoxin Postsynaptic neurotoxin Toxin
PTM	Amidation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	pathogenesis Inferred from electronic annotation. Source: InterPro synaptic transmission Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	extracellular region Inferred from electronic annotation. Source: InterPro postsynaptic membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	acetylcholine receptor inhibitor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 21

21

Potential

Propeptide

22 – 48

27

PRO_0000034881

Peptide

49 – 64

16

Alpha-conotoxin MII

PRO_0000034882

Amino acid modifications

Modified residue

64

1

Cysteine amide

Disulfide bond

50 ↔ 56

Disulfide bond

51 ↔ 64

Experimental info

Mutagenesis

53

1

N → A: Causes a >2700-fold reduction in activity at the alpha-3/beta-2 nAChR

Mutagenesis

54

1

P → A: Causes a 700-fold reduction in activity at the alpha-3/beta-2 nAChR

Mutagenesis

57

1

H → A: Causes a 17-fold reduction in activity at the alpha-3/beta-2 nAChR

Mutagenesis

60

1

H → A: Causes a 2700-fold reduction in activity at the alpha-3/beta-2 nAChR

Mutagenesis

63

1

L → A: Causes a 15-fold reduction in activity at the alpha-3/beta-2 nAChR

Secondary structure

1

.

.

.

.

.

.

68

Helix Strand Turn

Details...

Turn

50 – 52

3

Helix

55 – 59

5

Turn

60 – 63

4

Sequences

	Sequence		Length	Mass (Da)
	P56636-1 [UniParc]. Last modified September 5, 2006. Version 3. Checksum: FBD9AB40E6F277DF	FASTA	68	7,357
	10 20 30 40 50 60 MGMRMMFTVF LLVVLATTVV SFPSDRASDG RNAAANDKAS DVITLALKGC CSNPVCHLEH SNLCGRRR

References

[1]	"The A-superfamily of conotoxins: structural and functional divergence." Santos A.D., McIntosh J.M., Hillyard D.R., Cruz L.J., Olivera B.M. J. Biol. Chem. 279:17596-17606(2004) [PubMed: 14701840] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Venom duct.
[2]	"Alpha-conotoxin GIC from Conus geographus, a novel peptide antagonist of nicotinic acetylcholine receptors." McIntosh J.M., Dowell C., Watkins M., Garrett J.E., Yoshikami D., Olivera B.M. J. Biol. Chem. 277:33610-33615(2002) [PubMed: 12114524] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 28-68. Tissue: Hepatopancreas.
[3]	"A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors." Cartier G.E., Yoshikami D., Gray W.R., Luo S., Olivera B.M., McIntosh J.M. J. Biol. Chem. 271:7522-7528(1996) [PubMed: 8631783] [Abstract] Cited for: PROTEIN SEQUENCE OF 49-64, SYNTHESIS OF 49-64, AMIDATION AT CYS-64, DISULFIDE BONDS, MASS SPECTROMETRY, FUNCTION. Tissue: Venom.
[4]	"Human alpha6 AChR subtypes: subunit composition, assembly, and pharmacological responses." Kuryatov A., Olale F., Cooper J., Choi C., Lindstrom J. Neuropharmacology 39:2570-2590(2000) [PubMed: 11044728] [Abstract] Cited for: FUNCTION ON ALPHA-6 ACHR.
[5]	"Three-dimensional solution structure of alpha-conotoxin MII, an alpha3beta2 neuronal nicotinic acetylcholine receptor-targeted ligand." Shon K.-J., Koerber S.C., Rivier J.E., Olivera B.M., McIntosh J.M. Biochemistry 36:15693-15700(1997) [PubMed: 9398298] [Abstract] Cited for: STRUCTURE BY NMR OF 49-64, DISULFIDE BONDS.
[6]	"Three-dimensional solution structure of alpha-conotoxin MII by NMR spectroscopy: effects of solution environment on helicity." Hill J.M., Oomen C.J., Miranda L.P., Bingham J.-P., Alewood P.F., Craik D.J. Biochemistry 37:15621-15630(1998) [PubMed: 9843366] [Abstract] Cited for: STRUCTURE BY NMR OF 49-64, AMIDATION AT CYS-64, DISULFIDE BONDS.
[7]	"Engineering stable peptide toxins by means of backbone cyclization: stabilization of the alpha-conotoxin MII." Clark R.J., Fischer H., Dempster L., Daly N.L., Rosengren K.J., Nevin S.T., Meunier F.A., Adams D.J., Craik D.J. Proc. Natl. Acad. Sci. U.S.A. 102:13767-13772(2005) [PubMed: 16162671] [Abstract] Cited for: CYCLIZATION, STRUCTURE BY NMR OF 49-64, DISULFIDE BONDS.
[8]	"Determinants of potency on alpha-conotoxin MII, a peptide antagonist of neuronal nicotinic receptors." Everhart D., Cartier G.E., Malhotra A., Gomes A.V., McIntosh J.M., Luetje C.W. Biochemistry 43:2732-2737(2004) [PubMed: 15005608] [Abstract] Cited for: MUTAGENESIS OF ASN-53; PRO-54; HIS-57; HIS-60 AND LEU-63.

Cross-references

Sequence databases

PIR

A59046.

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1M2C	NMR	-	A	49-65	[»]
1MII	NMR	-	A	49-65	[»]
2AJW	NMR	-	A	49-68	[»]
2AK0	NMR	-	A	49-68	[»]

ModBase

Search...

Family and domain databases

InterPro

IPR009958. Conotoxin_a-typ.
[Graphical view]

Pfam

PF07365. Toxin_8. 1 hit.
[Graphical view]

PROSITE

PS60014. ALPHA_CONOTOXIN. 1 hit.
[Graphical view]

ProtoNet

Search...

Entry information

Entry name

CXA2_CONMA

Accession

Primary (citable) accession number: P56636

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 15, 1998
Last sequence update:	September 5, 2006
Last modified:	November 25, 2008
This is version 60 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)