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Structural basis of lariat RNA recognition by the intron debranching enzyme Dbr1.

Montemayor EJ, Katolik A, Clark NE, Taylor AB, Schuermann JP, Combs DJ, Johnsson R, Holloway SP, Stevens SW, Damha MJ, Hart PJ
Nucleic Acids Res 42 10845-55 (2014)
Related entries: 4pef, 4peh, 4pei

Cited: 32 times
EuropePMC logo PMID: 25123664

Abstract

The enzymatic processing of cellular RNA molecules requires selective recognition of unique chemical and topological features. The unusual 2',5'-phosphodiester linkages in RNA lariats produced by the spliceosome must be hydrolyzed by the intron debranching enzyme (Dbr1) before they can be metabolized or processed into essential cellular factors, such as snoRNA and miRNA. Dbr1 is also involved in the propagation of retrotransposons and retroviruses, although the precise role played by the enzyme in these processes is poorly understood. Here, we report the first structures of Dbr1 alone and in complex with several synthetic RNA compounds that mimic the branchpoint in lariat RNA. The structures, together with functional data on Dbr1 variants, reveal the molecular basis for 2',5'-phosphodiester recognition and explain why the enzyme lacks activity toward 3',5'-phosphodiester linkages. The findings illuminate structure/function relationships in a unique enzyme that is central to eukaryotic RNA metabolism and set the stage for the rational design of inhibitors that may represent novel therapeutic agents to treat retroviral infections and neurodegenerative disease.

Articles - 4peg mentioned but not cited (5)

  1. Structural basis of lariat RNA recognition by the intron debranching enzyme Dbr1. Montemayor EJ, Katolik A, Clark NE, Taylor AB, Schuermann JP, Combs DJ, Johnsson R, Holloway SP, Stevens SW, Damha MJ, Hart PJ. Nucleic Acids Res 42 10845-10855 (2014)
  2. Bifunctional inhibition of human immunodeficiency virus type 1 reverse transcriptase: mechanism and proof-of-concept as a novel therapeutic design strategy. Bailey CM, Sullivan TJ, Iyidogan P, Tirado-Rives J, Chung R, Ruiz-Caro J, Mohamed E, Jorgensen WL, Hunter R, Anderson KS. J Med Chem 56 3959-3968 (2013)
  3. A Switchable Palladium(II) Trefoil Entangled Tetrahedron with Temperature Dependence and Concentration Independence. Algar JL, Findlay JA, Evans JD, Preston D. Angew Chem Int Ed Engl 61 e202210476 (2022)
  4. Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase. Iyidogan P, Sullivan TJ, Chordia MD, Frey KM, Anderson KS. ACS Med Chem Lett 4 1183-1188 (2013)
  5. Nanoparticle role on the repeatability of stimuli-responsive nanocomposites. Ahn S, Lee SJ. Sci Rep 4 6624 (2014)


Reviews citing this publication (7)

  1. Metallophosphoesterases: structural fidelity with functional promiscuity. Matange N, Podobnik M, Visweswariah SS. Biochem J 467 201-216 (2015)
  2. Influenza Pathogenesis: The Effect of Host Factors on Severity of Disease. Gounder AP, Boon ACM. J Immunol 202 341-350 (2019)
  3. Specific labeling: An effective tool to explore the RNA world. Liu Y, Sousa R, Wang YX. Bioessays 38 192-200 (2016)
  4. Intronic RNA: Ad'junk' mediator of post-transcriptional gene regulation. Neil CR, Fairbrother WG. Biochim Biophys Acta Gene Regul Mech 1862 194439 (2019)
  5. Perspectives on Circular RNAs as Prostate Cancer Biomarkers. Fang J, Qi J, Dong X, Luo J. Front Cell Dev Biol 8 594992 (2020)
  6. Coupling and coordination in gene expression processes with pre-mRNA splicing. Pan K, Lee JT, Huang Z, Wong CM. Int J Mol Sci 16 5682-5696 (2015)
  7. Life and Death of mRNA Molecules in Entamoeba histolytica. Valdés-Flores J, López-Rosas I, López-Camarillo C, Ramírez-Moreno E, Ospina-Villa JD, Marchat LA. Front Cell Infect Microbiol 8 199 (2018)

Articles citing this publication (20)

  1. Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection. Zhang SY, Clark NE, Freije CA, Pauwels E, Taggart AJ, Okada S, Mandel H, Garcia P, Ciancanelli MJ, Biran A, Lafaille FG, Tsumura M, Cobat A, Luo J, Volpi S, Zimmer B, Sakata S, Dinis A, Ohara O, Garcia Reino EJ, Dobbs K, Hasek M, Holloway SP, McCammon K, Hussong SA, DeRosa N, Van Skike CE, Katolik A, Lorenzo L, Hyodo M, Faria E, Halwani R, Fukuhara R, Smith GA, Galvan V, Damha MJ, Al-Muhsen S, Itan Y, Boeke JD, Notarangelo LD, Studer L, Kobayashi M, Diogo L, Fairbrother WG, Abel L, Rosenberg BR, Hart PJ, Etzioni A, Casanova JL. Cell 172 952-965.e18 (2018)
  2. In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity. Pires DE, Chen J, Blundell TL, Ascher DB. Sci Rep 6 19848 (2016)
  3. Intron Lariat RNA Inhibits MicroRNA Biogenesis by Sequestering the Dicing Complex in Arabidopsis. Li Z, Wang S, Cheng J, Su C, Zhong S, Liu Q, Fang Y, Yu Y, Lv H, Zheng Y, Zheng B. PLoS Genet 12 e1006422 (2016)
  4. Metal dependence and branched RNA cocrystal structures of the RNA lariat debranching enzyme Dbr1. Clark NE, Katolik A, Roberts KM, Taylor AB, Holloway SP, Schuermann JP, Montemayor EJ, Stevens SW, Fitzpatrick PF, Damha MJ, Hart PJ. Proc Natl Acad Sci U S A 113 14727-14732 (2016)
  5. Mechanistic insights into the manganese-dependent phosphodiesterase activity of yeast Dbr1 with bis-p-nitrophenylphosphate and branched RNA substrates. Schwer B, Khalid F, Shuman S. RNA 22 1819-1827 (2016)
  6. Specific Recognition of a Single-Stranded RNA Sequence by a Synthetic Antibody Fragment. Shao Y, Huang H, Qin D, Li NS, Koide A, Staley JP, Koide S, Kossiakoff AA, Piccirilli JA. J Mol Biol 428 4100-4114 (2016)
  7. Crystal structure of the Entamoeba histolytica RNA lariat debranching enzyme EhDbr1 reveals a catalytic Zn2+ /Mn2+ heterobinucleation. Ransey E, Paredes E, Dey SK, Das SR, Heroux A, Macbeth MR. FEBS Lett 591 2003-2010 (2017)
  8. Arm-specific cleavage and mutation during reverse transcription of 2΄,5΄-branched RNA by Moloney murine leukemia virus reverse transcriptase. Döring J, Hurek T. Nucleic Acids Res 45 3967-3984 (2017)
  9. Design, Synthesis, and Properties of Phosphoramidate 2',5'-Linked Branched RNA: Toward the Rational Design of Inhibitors of the RNA Lariat Debranching Enzyme. Tago N, Katolik A, Clark NE, Montemayor EJ, Seio K, Sekine M, Hart PJ, Damha MJ. J Org Chem 80 10108-10118 (2015)
  10. Postsplicing-Derived Full-Length Intron Circles in the Protozoan Parasite Entamoeba histolytica. Mendoza-Figueroa MS, Alfonso-Maqueira EE, Vélez C, Azuara-Liceaga EI, Zárate S, Villegas-Sepúlveda N, Saucedo-Cárdenas O, Valdés J. Front Cell Infect Microbiol 8 255 (2018)
  11. Restriction of an intron size en route to endothermy. Královičová J, Borovská I, Pengelly R, Lee E, Abaffy P, Šindelka R, Grutzner F, Vořechovský I. Nucleic Acids Res 49 2460-2487 (2021)
  12. A functional link between lariat debranching enzyme and the intron-binding complex is defective in non-photosensitive trichothiodystrophy. Townley BA, Buerer L, Tsao N, Bacolla A, Mansoori F, Rusanov T, Clark N, Goodarzi N, Schmidt N, Srivatsan SN, Sun H, Sample RA, Brickner JR, McDonald D, Tsai MS, Walter MJ, Wozniak DF, Holehouse AS, Pena V, Tainer JA, Fairbrother WG, Mosammaparast N. Mol Cell 83 2258-2275.e11 (2023)
  13. Crystal Structure of the RNA Lariat Debranching Enzyme Dbr1 with Hydrolyzed Phosphorothioate RNA Product. Clark NE, Katolik A, Welch A, Schorl C, Holloway SP, Schuermann JP, Hart PJ, Taylor AB, Damha MJ, Fairbrother WG. Biochemistry 61 2933-2939 (2022)
  14. Intron turnover is essential to the development and pathogenicity of the plant pathogenic fungus Fusarium graminearum. Choi Y, Lee HH, Park J, Kim S, Choi S, Moon H, Shin J, Kim JE, Choi GJ, Seo YS, Son H. Commun Biol 5 1129 (2022)
  15. The Role of DBR1 as a Candidate Prognosis Biomarker in Esophageal Squamous Cell Carcinoma. Xu X, Yang X, Liu X, Bi Y, Kong P, Wang Y, Cheng X, Xi Y. Technol Cancer Res Treat 21 15330338221083105 (2022)
  16. Trichothiodystrophy-associated MPLKIP maintains DBR1 levels for proper lariat debranching and ectodermal differentiation. Theil AF, Pines A, Kalayci T, Heredia-Genestar JM, Raams A, Rietveld MH, Sridharan S, Tanis SE, Mulder KW, Büyükbabani N, Karaman B, Uyguner ZO, Kayserili H, Hoeijmakers JH, Lans H, Demmers JA, Pothof J, Altunoglu U, El Ghalbzouri A, Vermeulen W. EMBO Mol Med 15 e17973 (2023)
  17. Unexplored Molecular Features of the Entamoeba histolytica RNA Lariat Debranching Enzyme Dbr1 Expression Profile. Valdés J, Ortuño-Pineda C, Saucedo-Cárdenas O, Mendoza-Figueroa MS. Front Cell Infect Microbiol 8 228 (2018)
  18. A founder DBR1 variant causes a lethal form of congenital ichthyosis. Shamseldin HE, Sadagopan M, Martini J, Al-Ali R, Radefeldt M, Ataei M, Lemke S, Rahbeeni Z, Al Mutairi F, Ababneh F, AlRukban HA, Abdulwahab F, Alhajj SM, Bauer P, Bertoli-Avella A, Alkuraya FS. Hum Genet 142 1491-1498 (2023)
  19. Activation of human RNA lariat debranching enzyme Dbr1 by binding protein TTDN1 occurs though an intrinsically disordered C-terminal domain. Clark NE, Katolik A, Gallant P, Welch A, Murphy E, Buerer L, Schorl C, Naik N, Naik MT, Holloway SP, Cano K, Weintraub ST, Howard KM, Hart PJ, Jogl G, Damha MJ, Fairbrother WG. J Biol Chem 299 105100 (2023)
  20. Circular stable intronic RNAs possess distinct biological features and are deregulated in bladder cancer. Rasmussen AM, Okholm TLH, Knudsen M, Vang S, Dyrskjøt L, Hansen TB, Pedersen JS. NAR Cancer 5 zcad041 (2023)


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