{PDOC60018}
{PS60018; DELTA_ACTX}
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* Delta-atracotoxin (ACTX) family signature *
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Delta-atracotoxins (ACTXs)  are  peptide  toxins  isolated  from  the venom of
Australian funnel-web  spiders  that  inhibit conversion of the sodium channel
from the  open to the inactivated state, resulting in sodium current remaining
at membrane  potentials  where  inactivation is normally complete. They induce
spontaneous repetitive  firing and prolongation of action potentials resulting
in neurotransmitter  release  from  somatic  and autonomic nerve endings. This
results from  a  selective  slowing of tetrodotoxin (TTX) voltage-gated sodium
channel inactivation  and a hyperpolarizing shift of the voltage-dependence of
activation. This  action  is  due  to  voltage-dependent binding to neurotoxin
receptor site-3 [1,2].

All delta-ACTXs  are highly homologous 42-residue peptides with no significant
sequence homology with any presently known neurotoxins. The toxins have a high
proportion of   basic   residues   and  are  cross-linked  by  four  conserved
intramolecular disulfide  bonds.  Delta-ACTXs  comprise  a  core  beta  region
containing a   triple-stranded   antiparallel   beta-sheet  and  a  thumb-like
extension protruding  from  the  beta  region  (see <PDB:VTX>) [1,2]. The beta
region of  delta-ACTXs  contains  a  'disulfide-knot',  which places them in a
class of  toxins  and inhibitory polypeptides with 'an inhibitor cystine-knot'
(ICK) motif [3].

The delta-ACTX family includes:

 - Delta-ACTX-Ar1 (Robustoxin) from Atrax robustus (Funnel-web spider),
 - Delta-ACTX-Hv1  (versutoxin)  and  Delta-ACTX-Hv1b  from Hadronyche versuta
   Blue mountains funnel-web spider) (Atrax versutus).
 - Neurotoxin Magi 4 from Macrothele gigas (Spider),
 - Delta-missulenatoxin-Mb1a from Missulena bradleyi (Eastern mouse spider),

Delta-ACTX family  proteins  have  a [C-C-CCC-C-C-C] cysteine arrangement. The
three dimensional  structure  of delta-ACTXs possesses a knottin scaffold (see
<PDOC60004>) [E1]  with  a fourth pair (I-IV) of cysteine residues (marked '#'
in the following schematic representation) involved in an additional disulfide
linkage. The  cystine-knot  motif  in  delta-ACTXs provides high stability and
maintains the tertiary structure.

                              +----------------+
                              | +--------------|-----------+
                 #            |#|              |           |
                 CxxxxxxCxxxxxCCCxxxCxxxxxxxxxxCxxxxxxxxxxxC
                 |      |      |    |
                 +------|------+    |
                        +-----------+

'C': conserved cysteine involved in disulfide bond
'#': fourth pair of the cysteine residue

Our signature  pattern  for delta-ACTXs contains the eight conserved cysteines
involved in disulfide bonds.

-Conserved pattern: C-x(5)-W-C-x(4)-D-C-C-C-x(3)-C-x(2)-A-W-Y-x(5)-C-x(10,11)-
                    C
                    [The 8 C's are involved in disulfide bonds]
-Sequences known to belong to this class detected by the pattern: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Last update: June 2005 / First entry.

[ 1] Szeto T.H., Birinyi-Strachan L.C., Smith R., Connor M., Christie M.J.,
     King G.F., Nicholson G.M.
     "Isolation and pharmacological characterisation of
     delta-atracotoxin-Hv1b, a vertebrate-selective sodium channel toxin."
     FEBS Lett. 470:293-299(2000).
     PubMed=10745084
[ 2] Nicholson G.M., Little M.J., Birinyi-Strachan L.C.
     "Structure and function of delta-atracotoxins: lethal neurotoxins
     targeting the voltage-gated sodium channel."
     Toxicon 43:587-599(2004).
     PubMed=15066415; DOI=10.1016/j.toxicon.2004.02.006
[ 3] Pallaghy P.K., Nielsen K.J., Craik D.J., Norton R.S.
     "A common structural motif incorporating a cystine knot and a
     triple-stranded beta-sheet in toxic and inhibitory polypeptides."
     Protein Sci. 3:1833-1839(1994).
     PubMed=7849598
[E1] https://bioserv.cbs.cnrs.fr

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