Title : Structural basis of reduction-dependent activation of human
cystatin F .
Cystatins are important natural
cysteine protease inhibitors targeting primarily papain-like
cysteine proteases, including
cathepsins and parasitic proteases like cruzipain, but also mammalian
asparaginyl endopeptidase
Abstract :
- Mammalian cystatin F , which is expressed almost exclusively in hematopoietic cells and accumulates in lysosome-like organelles, has been implicated in the regulation of antigen presentation and other immune processes
- It is an unusual cystatin superfamily member with a redox-regulated activation mechanism and a restricted specificity profile
- We describe the 2.1A crystal structure of human cystatin F in its dimeric "off" state
- The two monomers interact in a fashion not seen before for cystatins or cystatin-like proteins that is crucially dependent on an unusual intermolecular disulfide bridge, suggesting how reduction leads to monomer formation and activation
- Strikingly, core sugars for one of the two N-linked glycosylation sites of cystatin F are well ordered, and their conformation and interactions with the protein indicate that this unique feature of cystatin F may modulate its inhibitory properties, in particular its reduced affinity toward asparaginyl endopeptidase compared with other cystatins