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The structural and biochemical characterization of human RNase H2 complex reveals the molecular basis for substrate recognition and Aicardi-Goutières syndrome defects.
J Biol Chem 2011; 286(12):10540-50JB

Abstract

RNase H2 cleaves RNA sequences that are part of RNA/DNA hybrids or that are incorporated into DNA, thus, preventing genomic instability and the accumulation of aberrant nucleic acid, which in humans induces Aicardi-Goutières syndrome, a severe autoimmune disorder. The 3.1 Å crystal structure of human RNase H2 presented here allowed us to map the positions of all 29 mutations found in Aicardi-Goutières syndrome patients, several of which were not visible in the previously reported mouse RNase H2. We propose the possible effects of these mutations on the protein stability and function. Bacterial and eukaryotic RNases H2 differ in composition and substrate specificity. Bacterial RNases H2 are monomeric proteins and homologs of the eukaryotic RNases H2 catalytic subunit, which in addition possesses two accessory proteins. The eukaryotic RNase H2 heterotrimeric complex recognizes RNA/DNA hybrids and (5')RNA-DNA(3')/DNA junction hybrids as substrates with similar efficiency, whereas bacterial RNases H2 are highly specialized in the recognition of the (5')RNA-DNA(3') junction and very poorly cleave RNA/DNA hybrids in the presence of Mg(2+) ions. Using the crystal structure of the Thermotoga maritima RNase H2-substrate complex, we modeled the human RNase H2-substrate complex and verified the model by mutational analysis. Our model indicates that the difference in substrate preference stems from the different position of the crucial tyrosine residue involved in substrate binding and recognition.

Authors+Show Affiliations

Laboratory of Protein Structure, International Institute of Molecular and Cell Biology, Warsaw 02-109, Poland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21177858

Citation

Figiel, Małgorzata, et al. "The Structural and Biochemical Characterization of Human RNase H2 Complex Reveals the Molecular Basis for Substrate Recognition and Aicardi-Goutières Syndrome Defects." The Journal of Biological Chemistry, vol. 286, no. 12, 2011, pp. 10540-50.
Figiel M, Chon H, Cerritelli SM, et al. The structural and biochemical characterization of human RNase H2 complex reveals the molecular basis for substrate recognition and Aicardi-Goutières syndrome defects. J Biol Chem. 2011;286(12):10540-50.
Figiel, M., Chon, H., Cerritelli, S. M., Cybulska, M., Crouch, R. J., & Nowotny, M. (2011). The structural and biochemical characterization of human RNase H2 complex reveals the molecular basis for substrate recognition and Aicardi-Goutières syndrome defects. The Journal of Biological Chemistry, 286(12), pp. 10540-50. doi:10.1074/jbc.M110.181974.
Figiel M, et al. The Structural and Biochemical Characterization of Human RNase H2 Complex Reveals the Molecular Basis for Substrate Recognition and Aicardi-Goutières Syndrome Defects. J Biol Chem. 2011 Mar 25;286(12):10540-50. PubMed PMID: 21177858.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The structural and biochemical characterization of human RNase H2 complex reveals the molecular basis for substrate recognition and Aicardi-Goutières syndrome defects. AU - Figiel,Małgorzata, AU - Chon,Hyongi, AU - Cerritelli,Susana M, AU - Cybulska,Magdalena, AU - Crouch,Robert J, AU - Nowotny,Marcin, Y1 - 2010/12/22/ PY - 2010/12/24/entrez PY - 2010/12/24/pubmed PY - 2011/6/10/medline SP - 10540 EP - 50 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 286 IS - 12 N2 - RNase H2 cleaves RNA sequences that are part of RNA/DNA hybrids or that are incorporated into DNA, thus, preventing genomic instability and the accumulation of aberrant nucleic acid, which in humans induces Aicardi-Goutières syndrome, a severe autoimmune disorder. The 3.1 Å crystal structure of human RNase H2 presented here allowed us to map the positions of all 29 mutations found in Aicardi-Goutières syndrome patients, several of which were not visible in the previously reported mouse RNase H2. We propose the possible effects of these mutations on the protein stability and function. Bacterial and eukaryotic RNases H2 differ in composition and substrate specificity. Bacterial RNases H2 are monomeric proteins and homologs of the eukaryotic RNases H2 catalytic subunit, which in addition possesses two accessory proteins. The eukaryotic RNase H2 heterotrimeric complex recognizes RNA/DNA hybrids and (5')RNA-DNA(3')/DNA junction hybrids as substrates with similar efficiency, whereas bacterial RNases H2 are highly specialized in the recognition of the (5')RNA-DNA(3') junction and very poorly cleave RNA/DNA hybrids in the presence of Mg(2+) ions. Using the crystal structure of the Thermotoga maritima RNase H2-substrate complex, we modeled the human RNase H2-substrate complex and verified the model by mutational analysis. Our model indicates that the difference in substrate preference stems from the different position of the crucial tyrosine residue involved in substrate binding and recognition. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/21177858/The_structural_and_biochemical_characterization_of_human_RNase_H2_complex_reveals_the_molecular_basis_for_substrate_recognition_and_Aicardi_Goutières_syndrome_defects_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=21177858 DB - PRIME DP - Unbound Medicine ER -