PA clan of proteases

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The PA clan of proteases (Proteases of mixed nucleophile, clan A) is the largest group of related proteases defined by a shared three‑dimensional fold. They all have a core made of two β‑barrels and use a catalytic triad (an acid, a histidine, and a nucleophile) to cut peptide bonds. The nucleophile can be serine or cysteine, depending on the family.

Even though their sequences can be very different (sometimes less than 10% identical), PA proteases look alike and work in similar ways because of their conserved structure. Members come from plants, animals, fungi, bacteria, archaea, and viruses. In some viral proteases, such as TEV, a long loop forms a binding tunnel that tightly recognizes the substrate.

Within PA, families are labeled by the nucleophile: C for cysteine proteases and S for serine proteases. Most cellular PA proteases are serine proteases, while some viral PA proteases use cysteine. They have many roles, including blood clotting enzymes like thrombin, digestive enzymes like trypsin, snake venom proteases that affect clotting, and bacterial toxins that damage tissues. Many viruses also use PA proteases to process their polyproteins.

PA proteases show both divergent evolution of their active sites (the same fold with different nucleophiles) and convergent evolution in using a common catalytic strategy. Some members are pseudoenzymes that bind substrates but do not catalyze reactions.