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Protein splicing

  • RNA and Proteins
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Abstract

Protein splicing is a posttranslational process that results in excision of an internal protein region (intein) and ligation of its flanking sequences (exteins). As distinguished from other variants of protein processing, protein splicing does not require cofactors of enzymes. Protein splicing is catalyzed by an internal domain (so-called Hint domain) of the intein itself. The review considers the main regularities and molecular mechanisms of the process, as well as the functions of Hint domains in other protein families (Hh proteins, bacterial BIL domains, etc.). Studies of protein splicing are of importance from both theoretical and applied viewpoints. For instance, comparisons of the inteins found in different domains of life illustrate the role of horizontal transfer in intein spreading. A possible role of inteins in regulating several cell processes is discussed on the basis of recent data.

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References

  1. Kane P.M., Yamashiro C.T., Wolczyk D.F., Neff N., Goebl M., Stevens T.H. 1990. Protein splicing converts the yeast TFP1 gene product to the 69 kDA subunit of the vacuolar H+-adenosine triphosphatase. Science. 250, 651–657.

    Article  PubMed  CAS  Google Scholar 

  2. Anraku Y., Mizutani R., Satow Y. 2005. Protein splicing: Its discovery and structural insight into novel chemical mechanisms. IUBMB Life. 57, 563–574.

    PubMed  CAS  Google Scholar 

  3. Perler F., Davis E., Dean G., Gimble F., Jack W., Neff N., Noren C., Thorner J., Belfort M. 1994. Protein splicing elements: Inteins and exteins, a definition of terms, and recommended nomenclature. Nucleic Acids Res. 22, 1125–1127.

    Article  PubMed  CAS  Google Scholar 

  4. Klabunde T., Sharma S., Telenti A., Jacobs W., Sacchettini J. 1998. Crystal structure of GyrA intein from Mycobacterium xenopi reveals structural basis of protein splicing. Nature Struct. Biol. 5, 31–36.

    Article  PubMed  CAS  Google Scholar 

  5. Noren C., Wang J., Perler F. 2000. Dissecting the chemistry of protein splicing and its applications. Angew. Chem. Int. Ed. 39, 450–466.

    Article  CAS  Google Scholar 

  6. Perler F. 2005. Protein splicing mechanisms and applications. IUMBM Life. 57, 469–476.

    CAS  Google Scholar 

  7. Yang J., Meng Q., Liu X. 2004. Intein harbouring large tandem repeats in replicative DNA helicase of Trichodesmium erythraeum. Mol. Microbiol. 51, 1185–1192.

    Article  PubMed  CAS  Google Scholar 

  8. Pietrokovski S. 1994. Conserved sequence features of inteins (protein introns) and their use in identifying new inteins and related proteins. Protein Sci. 3, 2340–2350.

    PubMed  CAS  Google Scholar 

  9. Perler F. 2002. InBase, the intein database. Nucleic Acids Res. 30, 383–384.

    Article  PubMed  CAS  Google Scholar 

  10. Perler F., Olsen G., Adam E. 1997. Compilation and analysis of intein sequences. Nucleic Acids Res. 25, 1087–1093.

    Article  PubMed  CAS  Google Scholar 

  11. Pietrokovski S. 1998. Modular organization of inteins and C-terminal autocatalytic domains. Protein Sci. 7, 64–71.

    PubMed  CAS  Google Scholar 

  12. Ding Y., Xu M., Ghosh I., Chen X., Ferrandon S., Lesage G., Rao Z. 2003. Crystal structure of a miniintein reveals a conserved catalytic module involved in side chain cyclization of asparagine during protein splicing. J. Biol. Chem. 278, 3913–3914.

    Google Scholar 

  13. Matsumura H., Takahashi H., Inoue T., Yamamoto T., Hashimoto H., Nishioka M., Fujiwara S., Takagi M., Imanaka T., Kai Y. 2006. Crystal structure of intein homing endonuclease II encoded in DNA polymerase gene from hyperthermophilic archaeon Thermococcus kodakaraensis strain KOD1. Proteins. 63, 711–715.

    Article  PubMed  CAS  Google Scholar 

  14. Guhan N., Muniyappa K. 2003. Mycobacterium tuberculosis RecA intein, a LAGLIDADG homing endonuclease, displays Mn2+-and DNA-dependent ATPase activity. Nucleic Acids Res. 31, 4184–4191.

    Article  PubMed  CAS  Google Scholar 

  15. Ghosh I., Sun L., Xu M. 2001. Zinc inhibition of protein trans-splicing and identification of regions essential for splicing and association of a split intein. J. Biol. Chem. 276, 24,051–24,058.

    CAS  Google Scholar 

  16. Choi J.J., Nam K.H., Min B., Kim S.J., Soll D., Kwon S.T. 2006. Protein trans-splicing and characterization of a split family B-type DNA polymerase from the hyperthermophilic archaeal parasite Nanoarchaeum equitans. J. Mol. Biol. 356, 1093–1106.

    Article  PubMed  CAS  Google Scholar 

  17. Clarke N. 1994. A proposed mechanism for the self-splicing of proteins. Proc. Natl. Acad. Sci. USA. 91, 11,084–11,088.

    CAS  Google Scholar 

  18. Shao Y., Xu M., Paulus H. 1996. Protein splicing: Evidence for an N-O acyl rearrangement as the initial step in the splicing process. Biochemistry. 35, 3810–3815.

    Article  PubMed  CAS  Google Scholar 

  19. Mills K.V., Perler F.B. 2005. The mechanism of inteinmediated protein splicing: Variations on a theme. Protein Peptide Lett. 12, 751–755.

    Article  CAS  Google Scholar 

  20. Xu M.Q., Coimb D.G., Paulus H., Noren J.C., Shao Y., Perler F.B. 1994. Protein splicing: An analysis of the branched intermediate and its resolution by succnimide formation. EMBO J. 13, 5517–5522.

    PubMed  CAS  Google Scholar 

  21. Sun P., Ye S., Ferrandon S., Evans T.C., Xu M.Q., Rao Z. 2005. Crystal structures of an intein from the split dnaE gene of Synechocystis sp. PCC6803 reveal the catalytic model without the penultimate histidine and the mechanism of zinc ion inhibition of protein splicing. J. Mol. Biol. 353, 1093–1105.

    Article  PubMed  CAS  Google Scholar 

  22. Wang S., Liu X. 1997. Identification of an unusual intein in chloroplast ClpP protease of Chlamydomonas eugametos. J. Biol. Chem. 272. 11,869–11,873.

    CAS  Google Scholar 

  23. Perler F.B. 1999. A natural example of protein trans-splicing. Trends Biochem. Sci. 24, 209–211.

    Article  PubMed  CAS  Google Scholar 

  24. Khan M.S., Khalid A.M., Malik K.A. 2005. Intein-mediated protein trans-splicing and transgene containment in plastids. Trends Biotechnol. 23, 217–220.

    Article  PubMed  CAS  Google Scholar 

  25. Flick K.E., Jurica M.S., Monnat R.J., Stoddard B.L. 1998. DNA binding and cleavage by the nuclear intronencoded homing endonuclease I-PpoI. Nature. 394, 96–101.

    Article  PubMed  CAS  Google Scholar 

  26. Gimble F.S., Duan X., Hu D., Quiocho F.A. 1998. Identification of Lys-403 in the PI-SceI homing endonuclease as part of a symmetric catalytic center. J. Biol. Chem. 273, 30,524–30,529.

    Article  CAS  Google Scholar 

  27. Dalgaard J.Z., Klar A.J., Moser M., Holley W.R., Chatterjee A., Mian I.S. 1997. Statistical modeling and analysis of the LAGLIDADG family of site-specific endonucleases and indentification of an intein that encodes a site-specific endonuclease of the HNH family. Nucleic Acids Res. 25, 4626–4638.

    Article  PubMed  CAS  Google Scholar 

  28. Bakhrat A., Jurica M., Stoddard B., Raveh D. 2004. Homology modeling and nutational analysis of Ho endonuclease of yeast. Genetics. 166, 721–728.

    Article  PubMed  CAS  Google Scholar 

  29. He Z., Crist M., Yen H., Duan X., Quiocho F.A., Gimble F.S. 1998. Amino acid residues in both the protein splicing and endonuclease domains of the PI-SceI intein mediate DNA binding. J. Biol. Chem. 273, 4607–4615.

    Article  PubMed  CAS  Google Scholar 

  30. Lykke-Andersen J., Garrett R.A., Kjems J. 1996. Protein footprinting approach to mapping DNA binding sites of two archaeal homing enzymes: evidence for a two-domain protein structure. Nucleic Acids Res. 24, 3982–3989.

    Article  PubMed  CAS  Google Scholar 

  31. Hu D., Crist M., Duan X., Quiocho F.A., Gimble F.S. 2000. Probing the structure of the PI-SceI-DNA complex by affinity cleavage and affinity photocrosslinking. J. Biol. Chem. 275, 2705–2712.

    Article  PubMed  CAS  Google Scholar 

  32. Pietrokovski S. 2001. Intein spread and extinction in evolution. Trends Genet. 17, 465–472.

    Article  PubMed  CAS  Google Scholar 

  33. Adam E., Perler F. 2002. Development of a positive genetic selection system for inhibition of protein splicing using mycobacterial inteins in Escherichia coli DNA gyrase subinit A. J. Mol. Microbiol. Biotechnol. 4, 479–487.

    PubMed  CAS  Google Scholar 

  34. Hall T.M., Porter J.A., Young K.E., Koonin E.V., Beachy P.A., Leahy D.J. 1997. Crystal structure of a Hedgehog autoprocessing domain: homology between Hedgehog and self-splicing proteins. Cell. 91, 85–97.

    Article  PubMed  CAS  Google Scholar 

  35. Porter J.A., Ekker S.C., Park W.J., von Kessler D.P., Young K.E., Chen C.H., Ma Y., Wood A.S., Cotter R.J., Koonin E.V., Beachy P.A. 1996. Hedgehog patterning activity: Role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. Cell. 86, 21–34.

    Article  PubMed  CAS  Google Scholar 

  36. Komori K., Fujita N., Ichiyanagi K., Shinagawa H., Morikawa K., Ishino Y. 1999. PI-PfuI and PI-PfuII, intein-coded homing endonucleases from Pyrococcus furiosus. Nucleic Acids Res. 27, 4167–4182.

    Article  PubMed  CAS  Google Scholar 

  37. Butler M., Goodwin T., Poulter R. 2005. Two new fungal inteins. Yeast. 22, 493–501.

    Article  PubMed  CAS  Google Scholar 

  38. Butler M.I., Gray J., Goodwin T.J., Poulter R.T. 2006. The distribution and evolutionary history of the PRP8 intein. BMC Evol. Biol. 6, 42.

    Article  PubMed  Google Scholar 

  39. Bjornsdottir S.H., Blondal T., Hreggvidsson G.O., Eggertsson G., Petursdottir S., Hjorleifsdottir S., Thorbjarnardottir S.H., Kristjansson J.K. 2006. Rhodothermus marinus: Physiology and molecular biology. Extremophiles. 10, 1–16.

    Article  PubMed  CAS  Google Scholar 

  40. Khan M.S., Khalid A.M., Malik K.A. 2005. Intein-mediated protein trans-splicing and transgene containment in plastids. Trends Biotechnol. 23, 217–220.

    Article  PubMed  CAS  Google Scholar 

  41. Hertveldt K., Lavigne R., Pleteneva E., Sernova N., Kurochkina L., Korchevskii R., Robben J., Mesyanzhinov V., Krylov V.N., Volckaert G. 2005. Genome comparison of Pseudomonas aeruginosa large phages. J. Mol. Biol. 354, 536–545.

    PubMed  CAS  Google Scholar 

  42. Nagasaki K., Shirai Y., Tomaru Y., Nishida K., Pietrokovski S. 2005. Algal viruses with distinct intraspecies host specificities include identical intein elements. Appl. Environ. Microbiol. 71, 3599–3607.

    Article  PubMed  CAS  Google Scholar 

  43. Suhre K., Audic S., Claverie J.M. 2005. Mimivirus gene promoters exhibit an unprecedented conservation among all eukaryotes. Proc. Natl. Acad. Sci. USA. 102, 14689–14693.

    Article  PubMed  CAS  Google Scholar 

  44. Ogata H., Raoult D., Claverie J.M. 2005. A new example of viral intein in Mimivirus. Virol. J. 2, 1–7.

    Article  Google Scholar 

  45. Gogarten J., Senejani A., Zhaxybayeva O., Olendzenski L., Hilario E. 2002. Inteins: Stcructure, function, and evolution. Annu. Rev. Microbiol. 56, 263–287.

    Article  PubMed  CAS  Google Scholar 

  46. Liu X., Yang J., Meng Q. 2003. Four Inteins and three group II introns encoded in a bacterial ribonucleotide reductase gene. J. Biol. Chem. 278, 46,826–46,831.

    CAS  Google Scholar 

  47. Paulus H. 2001. Inteins as enzymes. Bioorg. Chem. 29, 119–129.

    Article  PubMed  CAS  Google Scholar 

  48. Paulus H. 2000. Protein splicing and related forms of protein autoprocessing. Annu. Rev. Biochem. 69, 447–496.

    Article  PubMed  CAS  Google Scholar 

  49. Ingham P.W., McMahon A.P. 2001. Hedgehog signaling in animal development: Paradigms and principles. Genes Devel. 15, 3059–3087.

    Article  PubMed  CAS  Google Scholar 

  50. Roessler E., Belloni E., Gaudenz K., Vargas F., Scherer S.W., Tsui L.C., Muenke M. 1997. Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly. Hum. Mol. Genet. 6, 1847–1853.

    Article  PubMed  CAS  Google Scholar 

  51. Amitai G., Belenkiy O., Dassa B., Shainskaya A., Pietrokovski S. 2003. Distribution and function of new bacterial intein-like protein domains. Mol. Microbiol. 47, 61–73.

    Article  PubMed  CAS  Google Scholar 

  52. Dassa B., Haviv H., Amitai G., Pietrokovski S., 2004. Protein splicing and auto-cleavage of bacterial inteinlike domain lacking a C′-flanking nucleophilic residue. J. Biol. Chem. 30, 32001–32007.

    Article  Google Scholar 

  53. Parkhill J., Achtman M., James K.D., Bentley S.D., Churcher C., Klee S.R. 2000. Complete DNA sequence of a serogroup A strain of Neisseria meningitides Z2491. Nature. 404, 502–506.

    Article  PubMed  CAS  Google Scholar 

  54. Salanoubat M., Genin S., Artiguenave F., Gouzy J., Mangenot S., Arlat M. 2001. Genome sequence of the plant pathogen Ralstonia solanacearum. Nature. 415, 497–502.

    Article  Google Scholar 

  55. Albert A., Dhanaraj V., Genschel U., Khan G., Ramjee M.K., Pulido R., Sibanda B.L., von Delft F., Witty M., Blundell T.L., Smith A.G., Abell C. 1998. Crystal structure of aspartate decarboxylase at 2.2 Å resolution provides evidence for an ester in protein self-processing. Nature Struct. Biol. 5, 289–293.

    Article  PubMed  CAS  Google Scholar 

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Original Russian Text © P.L. Starokadomskyy, 2007, published in Molekulyarnaya Biologiya, 2007, Vol. 41, No. 2, pp. 314–330.

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Starokadomskyy, P.L. Protein splicing. Mol Biol 41, 278–293 (2007). https://doi.org/10.1134/S0026893307020094

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