Title : Crystal structure of MHC class II-associated
p41 Ii Ii fragment bound to
cathepsin L reveals the structural basis for differentiation between
cathepsins L and S
Abstract :
- The lysosomal cysteine proteases cathepsins S and L play crucial roles in the degradation of the invariant chain during maturation of MHC class II molecules and antigen processing
- The p41 form of the invariant chain includes a fragment which specifically inhibits cathepsin L but not S
- The crystal structure of the p41 fragment , a homologue of the thyroglobulin type-1 domains , has been determined at 2.0 A resolution in complex with cathepsin L
- The structure of the p41 fragment demonstrates a novel fold, consisting of two subdomains, each stabilized by disulfide bridges
- The first subdomain is an alpha-helix-beta-strand arrangement, whereas the second subdomain has a predominantly beta-strand arrangement
- The wedge shape and three-loop arrangement of the p41 fragment bound to the active site cleft of cathepsin L are reminiscent of the inhibitory edge of cystatins , thus demonstrating the first example of convergent evolution observed in cysteine protease inhibitors
- However, the different fold of the p41 fragment results in additional contacts with the top of the R-domain of the enzymes , which defines the specificity-determining S2 and S1' substrate-binding sites
- This enables inhibitors based on the thyroglobulin type-1 domain fold, in contrast to the rather non-selective cystatins , to exhibit specificity for their target enzymes
Output (sent_index, trigger,
protein,
sugar,
site):
Output(Part-Of) (sent_index,
protein,
site):
- 0. p41 Ii, fragment
- 3. structure of the p41, fragment
- 3. thyroglobulin type-1, domains
- 4. structure of the p41, fragment
- 6. p41, fragment
- 7. enzymes, R-domain
- 7. p41, fragment
*Output_Site_Fusion* (sent_index,
protein,
sugar,
site):