The non-catalytic part of proteases frequently harbours domains responsible for regulation or targeting. Here, we describe a novel sequence motif conserved in proteins that belong to different protease superfamilies, the subtilases and Zn-containing metalloproteases. The structure of the transferrin receptor, a catalytically inactive member of the latter family, suggests that the protease-associated domain forms a lid structure that covers the active site. In addition to proteases, the domain is also found in two different families of plant vacuolar sorting receptors.