title: Unusual structural features revealed by the solution NMR structure of the NLRC5 caspase recruitment domain.
abstract: The cytosolic nucleotide-binding domain and leucine-rich repeat-containing receptors (NLRs) are key sensors for bacterial and viral invaders and endogenous stress signals. NLRs contain a varying N-terminal effector domain that regulates the downstream signaling events upon its activation and determines the subclass to which a NLR member belongs. NLRC5 contains an unclassified N-terminal effector domain that has been reported to interact downstream with the tandem caspase recruitment domain (CARD) of retinoic acid-inducible gene I (RIG-I). Here we report the solution structure of the N-terminal effector domain of NLRC5 and in vitro interaction experiments with the tandem CARD of RIG-I. The N-terminal effector domain of NLRC5 adopts a six α-helix bundle with a general death fold, though it displays specific structural features that are strikingly different from the CARD. Notably, α-helix 3 is replaced by an ordered loop, and α-helix 1 is devoid of the characteristic interruption. Detailed structural alignments between the N-terminal effector domains of NLRC5 with a representative of each death-fold subfamily showed that NLRC5 fits best to the CARD subfamily and can be called an atypical CARD. Due to the specific structural features, the atypical CARD also displays a different electrostatic surface. Because the shape and charge of the surface is crucial for the establishment of a homotypic CARD-CARD interaction, these specific structural features seem to have a significant effect on the interaction between the atypical CARD of NLRC5 and the tandem RIG-I CARD.
authors.affiliation: Institute of Biochemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Petrus G M
authors.initials: PG
authors.lastname: Gutte
authors.forename: Simon
authors.initials: S
authors.lastname: Jurt
authors.forename: Markus G
authors.initials: MG
authors.lastname: Grütter
authors.forename: Oliver
authors.initials: O
authors.lastname: Zerbe
mesh_terms: D000818:Animals; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics; D051379:Mice; D019906:Nuclear Magnetic Resonance, Biomolecular; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C548042:NLRC5 protein, human; C549161:NLRC5 protein, mouse; D011971:Receptors, Immunologic; C452820:RIGI protein, human; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases