Functional consequences of posttranslational isomerization of Ser46 in a calcium channel toxin.
The venom of the funnel-web spider Agelenopsis aperta contains several peptides that paralyze prey by blocking voltage-sensitive calcium channels. Two peptides, omega-Aga-IVB (IVB) and omega-Aga-IVC (IVC), have identical amino acid sequences, yet have opposite absolute configurations at serine 46. These toxins had similar selectivities for blocking voltage-sensitive calcium channel subtypes but different potencies for blocking P-type voltage-sensitive calcium channels in rat cerebellar Purkinje cells as well as calcium-45 influx into rat brain synaptosomes. An enzyme purified from venom converts IVC to IVB by isomerizing serine 46, which is present in the carboxyl-terminal tail, from the L to the D configuration. Unlike the carboxyl terminus of IVC, that of IVB was resistant to the major venom protease. These results show enzymatic activities in A. aperta venom being used in an unprecedented strategy for coproduction of necessary neurotoxins that possess enhanced stability and potency.
Heck
S D
SD
NPS Pharmaceuticals Incorporated, Salt Lake City, Utah 84108.
Siok
C J
CJ
Krapcho
K J
KJ
Kelbaugh
P R
PR
Thadeio
P F
PF
Welch
M J
MJ
Williams
R D
RD
Ganong
A H
AH
Kelly
M E
ME
Lanzetti
A J
AJ
D060848:Agatoxins; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D015220:Calcium Channels / Q000378:metabolism*; D007535:Isomerases / Q000378:metabolism; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D011689:Purkinje Cells / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000378:metabolism*; D013111:Spider Venoms / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism* / Q000633:toxicity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
D060848:Agatoxins; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D013111:Spider Venoms; C083855:omega-agatoxin-Aa4b; D012694:Serine; D007535:Isomerases; D002118:Calcium