ShK-Dap22, a Potent Kv1.3-specific Immunosuppressive Polypeptide

Developmental Biology of Neoplastic Growth

“…Analogs of ShK are currently in development for treating autoimmune diseases because they are able to preferentially inhibit the proliferation of antigen-activated T-lymphocytes. By blocking Kv1.3 channels the membrane potential of the lymphocyte is reduced and this indirectly reduces the Ca 2+ influx of required to stimulate proliferation (Kalman et al 1998;Kem et al 1999; Beeton et al 2006).…”

“…Other SAK-I peptides like ShK blocks Kv1.1,Kv1.3,Kv1.4 and Kv1.6 channels with picomolar affinities (Table 1) (Kalman et al 1998), and BgK inhibits Kv1.1, Kv1.2 and Kv1.3 currents at nanomolar concentrations (Cotton et al 1997). Binding studies using radioiodinated-peptides ( 125 I-BgK) also demonstrated a high affinity for Kv1.1, Kv1.2 and Kv1.6 channels ( Table 1).…”

“…They provide a molecular description for the interaction of toxin residues with the pore of the channel ( Fig. 2c) (Doyle et al 1998;Gilquin et al 2002;Kalman et al 1998;Lanigan et al 2002;). Since the different Kv1 subtypes are highly homologous (83% identity) in the P region, it is not really surprising that a single type of toxin can bind to several members of the Kv1 channel family (Alessandri-Haber et al 1999).…”

“…The toxin diad makes electrostatic interactions with carbonyl oxygen atoms of the conserved tyrosine residue (motif GYGD) in the channel selectivity filter. The functional diad K22-Y23 of ShK interacts with the Y in the GYGD motif of the Kv1.3 channel pore domain (Gasparini et al 2004;Kalman et al 1998;Lanigan et al 2002;). This key step is completed by hydrophobic interactions between residues F6 and Y26 in BgK, (Gilquin et al 2002), Y23 in ShK, (Lanigan et al 2002) (Fig.…”

“…Binding and electrophysiological studies have shown that ShK-Dap22 is a highly potent and selective blocker of the Kv1.3 channel with a 100-fold decreased affinity for Kv1.1, Kv1.4 and Kv1.6 channels (Kalman et al 1998). NMR studies have shown that the overall structures of ShK and ShK-Dap22 are quite similar, but there are differences in the side chains involved in Kv1.3 binding (Kalman et al 1998;. A high expression level of Kv1.3 is considered as a marker for activated effector memory T cells (T EM cells), which are involved in the pathogenesis of autoimmune diseases.…”