title: Interaction patches of procaspase-1 caspase recruitment domains (CARDs) are differently involved in procaspase-1 activation and receptor-interacting protein 2 (RIP2)-dependent nuclear factor κB signaling.
abstract: Protein interaction domains belonging to the death domain-fold superfamily are six-helix bundles that mediate the assembly of large protein complexes involved in apoptotic and inflammatory signaling. Typically, death domains (DDs), a subfamily of the death domain-fold superfamily, harbor six delineated interaction patches on their surfaces that mediate three distinct and conserved types of interaction designated as types I, II, and III. Here, we show that caspase recruitment domains (CARDs), another subfamily of the death domain-fold superfamily, multimerize by employing at least two of the three reported interaction types that were identified in DDs. On the one hand, the CARD of procaspase-1 binds the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) through a type I interaction that involves a patch surrounding residue Asp-27. On the other hand, the CARD of procaspase-1 auto-oligomerizes through a type III interaction involving a patch surrounding residue Arg-45. This oligomerization allows binding of receptor-interacting protein 2 (RIP2). In addition, we show that a 1:1 interaction between ASC and procaspase-1 is sufficient for procaspase-1 to gain proteolytic activity, whereas the formation of a higher order CARD complex involving ASC, procaspase-1, and RIP2 is required for effective procaspase-1-mediated NF-κB activation. These findings indicate that the CARD of procaspase-1 is differently involved in the formation of procaspase-1 activating platforms and procaspase-1-mediated, RIP2-dependent NF-κB activation.
authors.affiliation: Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB), B-9052 Ghent (Zwijnaarde), Belgium; Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent (Zwijnaarde), Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Kersse
authors.affiliation: Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium; Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
authors.affiliation: Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB), B-9052 Ghent (Zwijnaarde), Belgium; Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent (Zwijnaarde), Belgium.
authors.forename: Mathieu J M
authors.initials: MJM
authors.lastname: Bertrand
authors.affiliation: Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB), B-9052 Ghent (Zwijnaarde), Belgium; Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent (Zwijnaarde), Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Vanden Berghe
authors.affiliation: Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB), B-9052 Ghent (Zwijnaarde), Belgium; Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent (Zwijnaarde), Belgium. Electronic address: peter.vandenabeele@dmbr.vib-ugent.be.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
mesh_terms: D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization / Q000502:physiology*; D017434:Protein Structure, Tertiary; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D009097:Multienzyme Complexes; D016328:NF-kappa B; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D020170:Caspase 1