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Substrate-induced clustering activates Trim-Away of pathogens and proteins
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.07.28.225359v1?rss=1
Authors: Zeng, J., Santos, A. F., Mukadam, A., Osswald, M., Luptak, J., Jacques, D., Dickson, C., Renner, N., Johnson, C., Vaysburd, M., McEwan, W. A., Morais-de-Sa, E., Clift, D., James, L. C.
Abstract:
Trim-Away is a powerful new technology that exploits off-the-shelf antibodies and the E3 RING ligase and cytosolic antibody receptor TRIM21 to carry out rapid protein depletion. How TRIM21 is catalytically-activated upon substrate engagement during either its normal immune function or when re-purposed for targeted protein degradation is unknown. Here we show that a mechanism of substrate-induced clustering triggers intermolecular dimerization of the RING domain to switch on the ubiquitination activity of TRIM21 and induce an antiviral response or drive Trim-Away. We harness this mechanism to expand the Trim-Away toolbox with highly-active TRIM21-nanobody chimeras that can also be controlled optogenetically. This work provides a mechanism for cellular activation of TRIM RING ligases and has important implications for targeted protein degradation technologies.
Copy rights belong to original authors. Visit the link for more info
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Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.07.28.225359v1?rss=1
Authors: Zeng, J., Santos, A. F., Mukadam, A., Osswald, M., Luptak, J., Jacques, D., Dickson, C., Renner, N., Johnson, C., Vaysburd, M., McEwan, W. A., Morais-de-Sa, E., Clift, D., James, L. C.
Abstract:
Trim-Away is a powerful new technology that exploits off-the-shelf antibodies and the E3 RING ligase and cytosolic antibody receptor TRIM21 to carry out rapid protein depletion. How TRIM21 is catalytically-activated upon substrate engagement during either its normal immune function or when re-purposed for targeted protein degradation is unknown. Here we show that a mechanism of substrate-induced clustering triggers intermolecular dimerization of the RING domain to switch on the ubiquitination activity of TRIM21 and induce an antiviral response or drive Trim-Away. We harness this mechanism to expand the Trim-Away toolbox with highly-active TRIM21-nanobody chimeras that can also be controlled optogenetically. This work provides a mechanism for cellular activation of TRIM RING ligases and has important implications for targeted protein degradation technologies.
Copy rights belong to original authors. Visit the link for more info