Functionally unrelated signalling proteins contain a fold similar to Mg 2+-dependent endonucleases

Abstract

Here, I describe previously unidentified sequence and structural similarities between the family of Mg2+-dependent endonucleases and a divergent set of proteins that include phosphatases involved in cell-cycle regulation and signal transduction. The founding member of this endonuclease family is DNase I ( 1 Suck D. Oefner C. Structure of DNase I at 2.0 Å resolution suggests a mechanism for binding to and cutting DNA. Nature. 1986; 321: 620-625 Crossref PubMed Scopus (285) Google Scholar ), joined by apurinic/apyrimidinic (AP) DNA-repair endonucleases that include exonuclease III (Exo III) and major human AP endonuclease (HAP1). Despite having <20% sequence identity and different cleavage preferences, these nucleases share the same catalytic residues and contain a similar four-layered α/β sandwich motif 2 Mol C.D. et al. Structure and function of the multifunctional DNA-repair enzyme exonuclease III. Nature. 1995; 374: 381-386 Crossref PubMed Scopus (340) Google Scholar , 3 Gorman M.A. et al. The crystal structure of the human DNA repair endonuclease HAP1 suggests the recognition of extra-helical deoxyribose at DNA abasic sites. EMBO J. 1997; 16: 6548-6558 Crossref PubMed Scopus (288) Google Scholar . Recently, AP endonucleases were shown to have sequence similarity with the endonuclease domain of long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons 4 Feng Q. et al. Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell. 1996; 87: 905-916 Abstract Full Text Full Text PDF PubMed Scopus (843) Google Scholar and sphingomyelinases 5 Matsuo Y. et al. A distant evolutionary relationship between bacterial sphingomyelinase and mammalian DNase I. Protein Sci. 1996; 5: 2459-2467 Crossref PubMed Scopus (59) Google Scholar , indicating that this fold can be used for cleaving phosphoester bonds on different substrates.