2-5A-dependent ribonuclease; 2-5A-dependent Rnase; ribonuclease 4, IFN-induced; ribonuclease L; Rnase L (RNASEL)

Function: - endoribonuclease - functions in the interferon (IFN) antiviral response - in IFN-treated & virus infected cells, RNASEL probably mediates its antiviral effects through a combination of direct cleavage of single-stranded viral RNAs, inhibition of protein synthesis through the degradation of rRNA, induction of apoptosis, & induction of other antiviral genes - RNASEL mediated apoptosis is the result of a JNK-dependent stress-response pathway leading to cytochrome c release from mitochondria & caspase-dependent apoptosis - thus activation of RNASEL could lead to elimination of virus infected cells under some circumstances - might play a central role in the regulation of mRNA - turnover cleaves 3' of UpNp dimers, with preference for UU & UA sequences, to sets of discrete products ranging from between 4 & 22 nucleotides in length - after binding to 2-5A (5'-phosphorylated 2',5'-linked oligoadenylates) homodimerization & subsequent activation occurs - monomer (inactive) or homodimer (active) Cofactor: - Mn+2 or Mg⁺² required for optimal RNA cleavage rates Inhibition: - binding to ABCE1 inhibits RNASEL Structure: - the nine ankyrin repeats also called 2-5A sensor constitute the N-terminus 2-5A binding domain - the protein kinase domain is predicted to be catalytically inactive; it allows the homodimerization - the ribonuclease domain is located in the C-terminus - a single active nuclease domain in a dimer is sufficient for ribonuclease activity (putative) - belongs to the protein kinase superfamily - contains 9 ANK repeats - contains 1 KEN domain - contains 1 protein kinase domain Compartment: cytoplasm, mitochondria Expression: - expressed in spleen & thymus > prostate, testis, uterus, small intestine, colon & peripheral blood leukocytes - induced by interferons - virus replication in higher vertebrates is restrained by IFNs that cause cells to transcribe genes encoding antiviral proteins such as 2'-5' oligoadenylate synthetases - oligoadenylate synthetase is stimulated by dsRNA to produce 5'-phosphorylated, 2'-5'-linked oligoadenylates (2-5A), whose function is to activate RNASEL Pathology: - defects in RNASEL are a cause of susceptibility to prostate cancer hereditary type 1

General

ankyrin repeat domain protein (ANKRD) endoribonuclease oligomerizing protein zinc finger protein

Properties

SIZE: entity length = 741 aa MW = 84 kD COMPARTMENT: mitochondria cytoplasm MOTIF: ankyrin repeat NAME: ankyrin repeat SITE: 24-53 ankyrin repeat NAME: ankyrin repeat SITE: 58-87 ankyrin repeat NAME: ankyrin repeat SITE: 91-120 ankyrin repeat NAME: ankyrin repeat SITE: 124-153 ankyrin repeat NAME: ankyrin repeat SITE: 167-197 ankyrin repeat NAME: ankyrin repeat SITE: 201-234 2-5A binding (P-loop) 1 {229-242} ankyrin repeat NAME: ankyrin repeat SITE: 238-268 2-5A binding (P-loop) 2 {253-275} ankyrin repeat NAME: ankyrin repeat SITE: 272-301 ankyrin repeat NAME: ankyrin repeat SITE: 303-329 kinase domain SITE: 365-586 MOTIF: ATP-binding site NAME: ATP-binding site Zinc finger NAME: Zinc finger SITE: 395-444 EFFECTOR-BOUND: Zn+2 KEN {589-723}

Database Correlations

OMIM correlations MORBIDMAP 180435 UniProt Q05823 PFAM correlations Entrez Gene 6041 Kegg hsa:6041

References

UniProt :accession Q05823