On November 13th, Science Signaling magazine published as a cover article the collaborative research results of the research team of the Institute of Biophysics, Chinese Academy of Sciences Liu Yingfang and Cheng Genhong (Overseas Team of the Center for Infection and Immunity of the Institute of Biophysics, UCLA), entitled Single Amino Acid Substitutions Confer the Antiviral Activity of the TRAF3 Adaptor Protein onto TRAF5, the editor issued a comment entitled TRAF5 Becomes Antiviral during the same period.
The innate immune response and its regulatory mechanism are important directions for immunologists. TRAF family members are important linker proteins in the natural immune signaling pathway. They bind different signaling molecules through their TRAF domains and perform different functions. On the one hand, TRAF3 is involved in the non-classical NF-κB pathway; on the other hand, it can interact with proteins such as TRIF and Cardif to activate the expression of interferon. The TRAF domain of TRAF5, another member of the TRAF family, has high sequence homology with the TRAF domain of TRAF3. Previous structural predictions indicate that they have identical ligand binding pockets and hot spot residues. Interestingly, TRAF5 cannot bind Cardif, nor can it replace TRAF3 to activate the interferon pathway.
Cheng Genhong's research group and Liu Yingfang's research group worked closely together to study the molecular mechanism of TRAF3 and TRAF5 with such specificity through structural biology methods. They first analyzed the structure of TRAF3 / Cardif complex and TRAF5. Through structural comparison, they found that two residues Tyr440 and Phe473 outside the known TRAF binding pocket play a key role in the binding of TRAF3 to Cardif. In TRAF5, the amino acids at these two positions are exactly opposite, Phe429 and Tyr462 respectively. Structural analysis shows that these two amino acids of TRAF5 may prevent its binding to Cardif. Cell biology experiments prove that the Y440F and F473Y mutants of TRAF3 lose the ability to bind Cardif and activate interferon expression; meanwhile, the TRAF5 mutants F429Y and Y462F can bind Cardif like TRAF3 and activate interferon, thus gaining antiviral ability . These results indicate that changing a single amino acid can change the selectivity of TRAF protein, and further reveal the molecular regulation mechanism of interferon expression.
This achievement is an important new contribution to the long-term research of the TRAF family protein antivirus by Cheng Genhong's group; it is also the antiviral protein ZAP (NSMB. 2012; 19 (4): 430-5) and ISG54 (Cell Res . 2012; 22 (9): 1328-38.) After the research work, new progress has been made in the direction of innate immunity research. This research project was supported by the Ministry of Science and Technology, the National Natural Science Foundation of China and the Chinese Academy of Sciences. Shanghai Light Source SSRF and Japan KEK provided support for diffraction data collection.
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