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Structural localization of disease‐associated sequence variations in the NACHT and LRR domains of PYPAF1 and NOD2
Author(s) -
Albrecht Mario,
Domingues Francisco S.,
Schreiber Stefan,
Lengauer Thomas
Publication year - 2003
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(03)01222-5
Subject(s) - genetics , leucine rich repeat , biology , pyrin domain , sequence (biology) , sequence alignment , computational biology , peptide sequence , conserved sequence , protein domain , gene , protein family , cyclic nucleotide binding domain , receptor , inflammasome
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.