Basis for regulated RNA cleavage by functional analysis of RNase L and Ire1p.
RNase L and Ire1p are members of a superfamily of regulated endoribonucleases that play essential roles in mediating diverse types of cellular stress responses. 2'-5' oligoadenylates, produced in response to interferon treatment and viral double-stranded RNA, are necessary to activate RNase L. In contrast, unfolded proteins in the endoplasmic reticulum activate Ire1p, a transmembrane serine/threonine kinase and endoribonuclease. To probe their similarities and differences, molecular properties of wild-type and mutant forms of human RNase L and yeast Ire1p were compared. Surprisingly, RNase L and Ire1p showed mutually exclusive RNA substrate specificity and partially overlapping but not identical requirements for phylogenetically conserved amino acid residues in their nuclease domains. A functional model for RNase L was generated based on the comparative analysis with Ire1p that assigns novel roles for ankyrin repeats and kinase-like domains.
Dong
B
B
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Ohio 44195, USA.
Niwa
M
M
Walter
P
P
Silverman
R H
RH
D000595:Amino Acid Sequence; D017124:Conserved Sequence; D019281:Dimerization; D004722:Endoribonucleases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D009843:Oligoribonucleotides / Q000494:pharmacology; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D020871:RNA Stability; D012260:Ribonucleases / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D005656:Fungal Proteins; D008562:Membrane Glycoproteins; D009843:Oligoribonucleotides; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; C082863:IRE1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D012260:Ribonucleases; C031956:2-5A-dependent ribonuclease