Structural localization of disease-associated sequence variations in the NACHT and LRR domains of PYPAF1 and NOD2.
Several autoinflammatory diseases with distinct clinical manifestations have been associated with sequence variations in the gene products PYPAF1/CIAS1 and NOD2/CARD15. Both proteins belong to the PYD/CARD-containing family of apoptosis regulators and activators of pro-inflammatory caspases. To gain insight into the dysfunctional role of sequence alterations, we assembled a structure-based multiple sequence alignment of family members and related proteins. This allowed us to analyze the putative effect of the alterations on the function of nucleotide-binding (NACHT) and leucine-rich repeat (LRR) domains shared by the family members. In support of this analysis, we carefully selected template structures for the NACHT and LRR domains and mapped the genetic variations onto 3D domain models. Additionally, we propose a model of the NACHT and LRR domain complex. Our study revealed that many of the disease-associated sequence variants are located close to highly conserved sequence regions of functional relevance and are spatially adjacent in the predicted 3D structure. The implications on the domain functions such as NTP-hydrolysis or oligomerization are discussed.
Albrecht
Mario
M
Max-Planck-Institute for Informatics, Stuhlsatzenhausweg 85, 66123 Saarbrücken, Germany. mario.albrecht@mpi-sb.mpg.de
Domingues
Francisco S
FS
Schreiber
Stefan
S
Lengauer
Thomas
T
D000595:Amino Acid Sequence; D001327:Autoimmune Diseases / Q000235:genetics*; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053473:Nod2 Signaling Adaptor Protein; D009711:Nucleotides / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D017386:Sequence Homology, Amino Acid
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D009711:Nucleotides