Biochemical and structural aspects of the ATP-binding domain in inflammasome-forming human NLRP proteins.
Nucleotide-binding domain and leucine-rich repeat-containing receptors (NLRs) regulate innate immunity by activating inflammatory responses in a variety of biological systems following the recognition of pathogen- or disease-associated molecular patterns. NLRs are characterized by a central nucleotide-binding and oligomerization (NACHT) domain found in P-loop NTPases. In this review, we detail the functional and structural properties of the NACHT domain of a subfamily of NLRs, the NLRPs (NLR containing a pyrin domain), based on previous studies, sequence analysis, homology modeling, and structure predictions. Several NLRPs have been found to regulate inflammatory responses through the assembly of oligomeric caspase 1-activating platforms known as inflammasomes, the 3-dimensional structure of the NLRP NACHT domain has still not been solved. Homology modeling suggests that sequence variability within the NACHT domains of different NLRP family members may alter the topology of the ATP-binding pocket. Based on this finding, we discuss the potential therapeutic prospects aligned with the NACHT domain and the development of selective inhibitors of inflammasome activity.
Libin Cardiovascular Institute and Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, T2N 4Z6, Canada.
Justin A
JA
MacDonald
Champa P
CP
Wijekoon
Kuo-Chieh
KC
Liao
Daniel A
DA
Muruve
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D000070576:NLR Proteins; D043583:Nucleoside-Triphosphatase / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D058847:Inflammasomes; D000070576:NLR Proteins; C427903:NLRP1 protein, human; D000255:Adenosine Triphosphate; D043583:Nucleoside-Triphosphatase
NACHT domain; NLR; NLRP; STAND ATPase; nucleotide-binding