Abstract
Large mammalian proteins containing a nucleotide-binding domain (NBD) and C-terminal leucine-rich repeats (LRR) similar in structure to plant disease resistance proteins have been suggested as critical in innate immunity. Our interest in CIITA, a NBD/LRR protein, and recent reports linking mutations in two other NBD/LRR proteins to inflammatory disorders have prompted us to perform a search for other members. Twenty-two known and novel NBD/LRR genes are spread across eight human chromosomes, with multigene clusters occurring on 11, 16, and 19. Most of these are telomeric. Their N termini vary, but most have a pyrin domain. The genomic organization demonstrates a high degree of conservation of the NBD- and LRR-encoding exons. Except for CIITA, all the predicted NBD/LRR proteins are likely ATP-binding proteins. Some have broad tissue expression, whereas others are restricted to myeloid cells. The implications of these data on origins, expression, and function of these genes are discussed.
Highlights
We describe the identification of additional putative mammalian nucleotide-binding domain (NBD)/ leucine-rich repeats (LRR) proteins similar to the known family members
The N-terminal sequences of CIITA yielded no related sequences obviously belonging to an NBD/LRR protein
Pyrin and LRR sequences identified within contigs containing NBDs were examined for location and orientation to determine the likelihood of residing in the same operon as an identified NBD
Summary
Searches were performed using the published Celera human genome scaffold data [16], the National Center for Biotechnology Information (NCBI) “nr” database (containing GenBank, European Molecular Biology Laboratory, DNA Data Base in Japan, Protein Data Base, and completed phase 3 and 4 high-throughput genomic sequencing (HTGS) sequences), and the NCBI genome database, [17]. Initial searches were performed using the B cell form of CIITA protein sequence [1] as a query using the BLAST search algorithms BLASTP and TBLASTN (see supplemental data Fig. 1).. BLASTP identifies amino acid sequence similarities through query sequence comparison with database proteins and is more likely to find distant relationships than BLASTN [18]. TBLASTN compares the query protein sequence with translations of all six reading frames of available nucleotide sequences and has the same advantages as BLASTP. LRR sequences, the N-terminal pyrin domains of DEFCAP, and the CARD domains of Nod and Nod were used to perform similar searches. The N-terminal sequences of CIITA yielded no related sequences obviously belonging to an NBD/LRR protein
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