Structural and Biochemical Studies on Procaspase-8: New Insights on Initiator Caspase Activation
Caspases are proteases with an active-site cysteine and aspartate specificity in their substrates. They are involved in apoptotic cell death and inflammation, and dysfunction of these enzymes is directly linked to a variety of diseases. Caspase-8 initiates an apoptotic pathway triggered by external...
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| Veröffentlicht in: | Structure (London) 2009-03, Vol.17 (3), p.438-448 |
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| creator | Keller, Nadine Mareš, Jiří Zerbe, Oliver Grütter, Markus G. |
| description | Caspases are proteases with an active-site cysteine and aspartate specificity in their substrates. They are involved in apoptotic cell death and inflammation, and dysfunction of these enzymes is directly linked to a variety of diseases. Caspase-8 initiates an apoptotic pathway triggered by external stimuli. It was previously characterized in its active inhibitor bound state by crystallography. Here we present the solution structure of the monomeric unprocessed catalytic domain of the caspase-8 zymogen, procaspase-8, showing for the first time the position of the linker and flexibility of the active site forming loops. Biophysical studies of carefully designed mutants allowed disentangling dimerization and processing, and we could demonstrate lack of activity of monomeric uncleaved procaspase-8 and of a processed but dimerization-incompetent mutant. The data provide experimental support in so-far unprecedented detail, and reveal why caspase-8 (and most likely other initiator caspases) needs the dimerization platform during activation. |
| doi_str_mv | 10.1016/j.str.2008.12.019 |
| format | Article |
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| ispartof | Structure (London), 2009-03, Vol.17 (3), p.438-448 |
| issn | 0969-2126 1878-4186 |
| language | eng |
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| source | MEDLINE; Cell Press Free Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; ScienceDirect Journals (5 years ago - present); Free Full-Text Journals in Chemistry |
| subjects | Amino Acid Sequence Caspase 8 - chemistry Caspase 8 - metabolism Caspases - chemistry Caspases - metabolism Catalysis Dimerization Enzyme Activation Enzyme Precursors - chemistry Enzyme Precursors - metabolism Models, Molecular Molecular Sequence Data PROTEIN Protein Conformation Substrate Specificity |
| title | Structural and Biochemical Studies on Procaspase-8: New Insights on Initiator Caspase Activation |
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