Substrate-induced remodeling of the active site regulates human HTRA1 activity

• Published in: Nature structural & molecular biology Vol. 18; no. 3; pp. 386 - 388
• Main Authors: Clausen, Tim, Ehrmann, Michael, Truebestein, Linda, Tennstaedt, Annette, Mönig, Timon, Krojer, Tobias, Canellas, Flavia, Kaiser, Markus
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2011; Nature Publishing Group
• Subjects: 631/337/474; 631/45/535; 631/57/2272/2273; Binding sites; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; brief-communication; Catalytic Domain; Cellular signal transduction; Crystal structure; Crystallography, X-Ray; High-Temperature Requirement A Serine Peptidase 1; Humans; Hydrolysis; Life Sciences; Membrane Biology; Models, Molecular; Molecular biology; PDZ Domains; Physiological aspects; Proteases; Protein Binding; Protein Folding; Protein Structure; Proteins; Serine Endopeptidases - chemistry; Serine Endopeptidases - metabolism; Structure; Substrates; Germany
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.2013

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.