Structure of the perforin C2 domain. (Left) Alignment of the C2 domain of human perforin with C2 domains of known 3-dimensional structure (SYNI(A): first domain of synaptotagmin I, Protein Data Bank (pdb) identifier 1RSY; PKCβ: protein kinase C β, pdb identifier 1A25; cPLA2: cytoplasmic phospholipase A₂, pdb identifier 1rlw; PLCδ1: phosphoinositide-specific phospholipase C δ1, pdb identifier 1DJX). Identical amino acids are highlighted in black and similar amino acids are highlighted in gray. Mean positions of β-strands are indicated below the alignment, with labeling corresponding to the type I and type II topology. Amino acids that might be involved in calcium-binding sites are indicated by arrows (loop 1: D430, T433 [aligned with cPLA2 D40], D436 [the whole conformation of perforin loop 1 otherwise resembling more closely that of the loop 1 of synaptotagmin 1 C2A]; loop 2: D455 [aligned with cPLA2 N65]; loop 3: D484, D486, D492), whereas the position of the proline that is substituted by a leucine is shown by an asterisk. (Right) Model of the 3-dimensional structure of human perforin based on the proposed structure of cPLA2. Amino acids that might be involved in calcium binding are indicated, as are N458 and P459. Strands are labeled according to the type II topology, as predicted for human perforin.