Peptide inhibitors: Four of a kind beats a pair

Abstract

The proapoptotic cysteine protease caspase-6 participates in the neuropathology of several diseases. Unlike the active dimeric form, the caspase-6 zymogen forms a unique tetramer that can be stabilized by allosteric inhibitors, which prevents caspase-6 activation.

Figure 1

The caspase-6 zymogen forms a tetramer that is stabilized by pep419. (a) In this structure of the caspase-6 dimer, the large and small subunits are shown in red and orange, respectively. The intersubunit linker is shown in magenta; the single β-sheet, containing the ¹⁹⁰TEVD¹⁹³ cleavage site, is inserted into the active site of the enzyme. The region of the large subunit, containing the residues that interact with pep419, is shown in blue. (b) The A-C and B-D chains of two caspase-6 zymogen dimers face one another to form the tetramer, which is stabilized by pep419 (green). Renderings of the dimeric caspase-6 zymogen (Protein Data Bank code 3NR2) were performed using UCSF Chimera.