Abstract
Crystal structures of active and inactive conformations of the human serine protease HTRA1 reveal that substrate binding to the active site is sufficient to stimulate proteolytic activity. HTRA1 attaches to liposomes, digests misfolded proteins into defined fragments and undergoes substrate-mediated oligomer conversion. In contrast to those of other serine proteases, the PDZ domain of HTRA1 is dispensable for activation or lipid attachment, indicative of different underlying mechanistic features.
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Acknowledgements
We thank D. Hellerschmied for help with biochemical assays. M.E. was supported by the Deutsche Forschungsgemeinschaft and T.C. by ERA-Net NEURON, FWF I 235-B09.
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L.T., A.T., T.M. and F.C. performed experiments; L.T. and T.K. solved the structures; L.T., M.K., T.C. and M.E. planned the experiments and wrote the paper.
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Supplementary Figures 1–4, Supplementary Notes, Supplementary Table 1 and Supplementary Methods (PDF 1620 kb)
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Truebestein, L., Tennstaedt, A., Mönig, T. et al. Substrate-induced remodeling of the active site regulates human HTRA1 activity. Nat Struct Mol Biol 18, 386–388 (2011). https://doi.org/10.1038/nsmb.2013
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DOI: https://doi.org/10.1038/nsmb.2013
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