Structural highlights
Function
[SPI2_CWPXB] Specific and potent inhibitor of the interleukin-1-beta converting enzyme (ICE) thereby suppressing an interleukin-1 beta response to infection. The inhibition of ICE by crmA is an example of a "cross-class" interaction, in which a serpin inhibits a non-serine proteinase. Also inhibits granzyme B.[1] [2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
BACKGROUND: Cowpox virus expresses the serpin CrmA (cytokine response modifier A) in order to avoid inflammatory and apoptotic responses of infected host cells. The targets of CrmA are members of the caspase family of proteases that either initiate the extrinsic pathway of apoptosis (caspases 8 and 10) or trigger activation of the pro-inflammatory cytokines interleukin-1beta and interleukin-18 (caspase 1). RESULTS: We have determined the structure of a cleaved form of CrmA to 2.26 A resolution. CrmA has the typical fold of a cleaved serpin, even though it lacks the N-terminal half of the A helix, the entire D helix, and a portion of the E helix that are present in all other known serpins. The reactive-site loop of CrmA was mutated to contain the optimal substrate recognition sequence for caspase 3; however, the mutation only marginally increased the ability of CrmA to inhibit caspase 3. Superposition of the reactive-site loop of alpha1-proteinase inhibitor on the cleaved CrmA structure provides a model for virgin CrmA that can be docked to caspase 1, but not to caspase 3. CONCLUSIONS: CrmA exemplifies viral economy, selective pressure having resulted in a 'minimal' serpin that lacks the regions not needed for structural integrity or inhibitory activity. The docking model provides an explanation for the selectivity of CrmA. Our demonstration that engineering optimal substrate recognition sequences into the CrmA reactive-site loop fails to generate a good caspase 3 inhibitor is consistent with the docking model.
Crystal structure of the apoptotic suppressor CrmA in its cleaved form.,Renatus M, Zhou Q, Stennicke HR, Snipas SJ, Turk D, Bankston LA, Liddington RC, Salvesen GS Structure. 2000 Jul 15;8(7):789-97. PMID:10903953[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ray CA, Black RA, Kronheim SR, Greenstreet TA, Sleath PR, Salvesen GS, Pickup DJ. Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1 beta converting enzyme. Cell. 1992 May 15;69(4):597-604. PMID:1339309
- ↑ Komiyama T, Ray CA, Pickup DJ, Howard AD, Thornberry NA, Peterson EP, Salvesen G. Inhibition of interleukin-1 beta converting enzyme by the cowpox virus serpin CrmA. An example of cross-class inhibition. J Biol Chem. 1994 Jul 29;269(30):19331-7. PMID:8034697
- ↑ Renatus M, Zhou Q, Stennicke HR, Snipas SJ, Turk D, Bankston LA, Liddington RC, Salvesen GS. Crystal structure of the apoptotic suppressor CrmA in its cleaved form. Structure. 2000 Jul 15;8(7):789-97. PMID:10903953
