Protein splicing: How Inteins escape from precursor proteins

Journal of Biological Chemistry

Volumn 289, Issue 21, 2014, Pages 14498-14505

  Mills, Kenneth V ^a   Johnson, Margaret A ^b   Perler, Francine B ^c  

^a Department of Biology   (United States)

^b UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

^c NEW ENGLAND BIOLABS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACIDS; ENZYMES; PROTEINS; SUBSTITUTION REACTIONS; SUBSTRATES;

COVALENTLY LINKED SUBSTRATES; EXTEINS; HOST PROTEINS; INTEINS; NUCLEOPHILIC DISPLACEMENT; PRECURSOR PROTEINS; PROTEIN-SPLICING; SUBSTRATE BINDING;

COORDINATION REACTIONS;

ENDONUCLEASE; INTEIN; NUCLEOPHILE; PROTEIN PRECURSOR; SONIC HEDGEHOG PROTEIN;

AMINO ACID SEQUENCE; CATALYSIS; CONFORMATIONAL TRANSITION; ENZYME ACTIVE SITE; ENZYME KINETICS; ENZYME SUBSTRATE COMPLEX; NONHUMAN; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN DOMAIN; PROTEIN FOLDING; PROTEIN MOTIF; PROTEIN PROCESSING; REVIEW; TRANSESTERIFICATION;

ASPARAGINE CYCLIZATION; BACTERIAL INTEIN-LIKE DOMAIN; ENZYME KINETICS; ENZYME MECHANISMS; HEDGEHOG; INTEIN; POST-TRANSLATIONAL MODIFICATION; PROTEIN MOTIFS; PROTEIN SPLICING; THIOESTER;

AMINO ACIDS; EXTEINS; INTEINS; MODELS, GENETIC; MOLECULAR STRUCTURE; PROTEIN PRECURSORS; PROTEIN SPLICING; PROTEINS;

EID: 84901468888     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.R113.540310     Document Type: Review

References (100)

1. Shih, C. K., Wagner, R., Feinstein, S., Kanik-Ennulat, C., and Neff, N. (1988) A dominant trifluoperazine resistance gene from Saccharomyces cerevisiae has homology with F0F1 ATP synthase and confers calcium-sensitive growth. Mol. Cell. Biol. 8, 3094-3103 .
2. +-translocating adenosine triphosphatase from vacuolar membranes of Saccharomyces cerevisiae. J. Biol. Chem. 265, 6726-6733 .
3. +-adenosine triphosphatase. Science 250, 651-657 . (Pubitemid 120034281)
4. Perler, F. B., Davis, E. O., Dean, G. E., Gimble, F. S., Jack, W. E., Neff, N., Noren, C. J., Thorner, J., and Belfort, M. (1994) Protein splicing elements: inteins and exteins: a definition of terms and recommended nomenclature. Nucleic Acids Res. 22, 1125-1127 . (Pubitemid 24162112)
5. Davis, E. O., Jenner, P. J., Brooks, P. C., Colston, M. J., and Sedgwick, S. G. (1992) Protein splicing in the maturation of M. tuberculosis recA protein: a mechanism for tolerating a novel class of intervening sequence. Cell 71, 201-210 .
6. Hodges, R. A., Perler, F. B., Noren, C. J., and Jack, W. E. (1992) Protein splicing removes intervening sequences in an archaea DNA polymerase. Nucleic Acids Res. 20, 6153-6157 . (Pubitemid 23039139)
7. Xu, M. Q., Southworth, M. W., Mersha, F. B., Hornstra, L. J., and Perler, F. B. (1993) In vitro protein splicing of purified precursor and the identification of a branched intermediate. Cell 75, 1371-1377 . (Pubitemid 24021911)
8. Paulus, H. (2001) Inteins as enzymes. Bioorg. Chem. 29, 119-129 . (Pubitemid 34226233)
9. Evans, T. C., Jr., and Xu, M. Q. (1999) Intein-mediated protein ligation: harnessing nature's escape artists. Biopolymers 51, 333-342 . (Pubitemid 30117293)
10. Tori, K., Dassa, B., Johnson, M. A., Southworth, M. W., Brace, L. E., Ishino, Y., Pietrokovski, S., and Perler, F. B. (2010) Splicing of the mycobacteriophage Bethlehem DnaB intein: identification of a new mechanistic class of inteins that contain an obligate block F nucleophile. J. Biol. Chem. 285, 2515-2526 .
11. Xu, M. Q., Comb, D. G., Paulus, H., Noren, C. J., Shao, Y., and Perler, F. B. (1994) Protein splicing: an analysis of the branched intermediate and its resolution by succinimide formation. EMBO J. 13, 5517-5522 . (Pubitemid 24363018)
12. Shao, Y., Xu, M. Q., and Paulus, H. (1995) Protein splicing: characterization of the aminosuccinimide residue at the carboxyl terminus of the excised intervening sequence. Biochemistry 34, 10844-10850 .
13. Chong, S., Shao, Y., Paulus, H., Benner, J., Perler, F. B., and Xu, M. Q. (1996) Protein splicing involving the Saccharomyces cerevisiae VMA intein: the steps in the splicing pathway, side reactions leading to protein cleavage, and establishment of an in vitro splicing system. J. Biol. Chem. 271, 22159-22168 . (Pubitemid 26303848)
14. Xu, M. Q., and Perler, F. B. (1996) The mechanism of protein splicing and its modulation by mutation. EMBO J. 15, 5146-5153 . (Pubitemid 26336196)
15. Cooper, A. A., Chen, Y. J., Lindorfer, M. A., and Stevens, T. H. (1993) Protein splicing of the yeast TFP1 intervening protein sequence: a model for self-excision. EMBO J. 12, 2575-2583 . (Pubitemid 23194209)
16. Shao, Y., Xu, M. Q., and Paulus, H. (1996) Protein splicing: evidence for an N-O acyl rearrangement as the initial step in the splicing process. Biochemistry 35, 3810-3815 . (Pubitemid 26102171)
17. Pietrokovski, S. (2001) Intein spread and extinction in evolution. Trends Genet. 17, 465-472 . (Pubitemid 32727239)
18. Perler, F. B., Olsen, G. J., and Adam, E. (1997) Compilation and analysis of intein sequences. Nucleic Acids Res. 25, 1087-1093 . (Pubitemid 27303196)
19. 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 .
20. Perler, F. B. (2002) InBase: the Intein Database. Nucleic Acids Res. 30, 383-384 .
21. Novikova, O., Topilina, N., and Belfort, M. (2014) Enigmatic distribution, evolution, and function of inteins. J. Biol. Chem. 289, 14490-14497 .
22. Gimble, F. S., and Thorner, J. (1992) Homing of a DNA endonuclease gene by meiotic gene conversion in Saccharomyces cerevisiae. Nature 357, 301-306 .
23. Derbyshire, V., Wood, D. W., Wu, W., Dansereau, J. T., Dalgaard, J. Z., and Belfort, M. (1997) Genetic definition of a protein-splicing domain: functional mini-inteins support structure predictions and a model for intein evolution. Proc. Natl. Acad. Sci. U.S.A. 94, 11466-11471 .
24. Telenti, A., Southworth, M., Alcaide, F., Daugelat, S., Jacobs, W. R., Jr., and Perler, F. B. (1997) The Mycobacterium xenopi GyrA protein splicing element: characterization of a minimal intein. J Bacteriol. 179, 6378-6382 . (Pubitemid 27443920)
25. Mills, K. V., Lew, B. M., Jiang, S., and Paulus, H. (1998) Protein splicing in trans by purified N-and C-terminal fragments of the Mycobacterium tuberculosis RecA intein. Proc. Natl. Acad. Sci. U.S.A. 95, 3543-3548 . (Pubitemid 28173164)
26. Hiraga, K., Derbyshire, V., Dansereau, J. T., Van Roey, P., and Belfort, M. (2005) Minimization and stabilization of the Mycobacterium tuberculosis recA intein. J. Mol. Biol. 354, 916-926 . (Pubitemid 41735512)
27. Elleuche, S., Döring, K., and Pöggeler, S. (2008) Minimization of a eukaryotic mini-intein. Biochem. Biophys. Res. Commun. 366, 239-243 . (Pubitemid 50010678)
28. Wu, H., Hu, Z., and Liu, X. Q. (1998) Protein trans-splicing by a split intein encoded in a split DnaE gene of Synechocystis sp. PCC6803. Proc. Natl. Acad. Sci. U.S.A. 95, 9226-9231 .
29. Iwai, H., Züger, S., Jin, J., and Tam, P. H. (2006) Highly efficient protein trans-splicing by a naturally split DnaE intein from Nostoc punctiforme. FEBS Lett. 580, 1853-1858 .
30. Zettler, J., Schütz, V., and Mootz, H. D. (2009) The naturally split Npu DnaE intein exhibits an extraordinarily high rate in the protein transsplicing reaction. FEBS Lett. 583, 909-914 .
31. Caspi, J., Amitai, G., Belenkiy, O., and Pietrokovski, S. (2003) Distribution of split DnaE inteins in Cyanobacteria. Mol. Microbiol. 50, 1569-1577 . (Pubitemid 38010453)
32. Martin, D. D., Xu, M. Q., and Evans, T. C., Jr. (2001) Characterization of a naturally occurring trans-splicing intein from Synechocystis sp. PCC6803. Biochemistry 40, 1393-1402 . (Pubitemid 32142901)
33. Wood, D. W., and Camarero, J. A. (2014) Intein applications: from protein purification and labeling to metabolic control methods. J. Biol. Chem. 289, 14512-14519 .
34. Hall, T. M., Porter, J. A., Young, K. E., Koonin, E. V., Beachy, P. A., and Leahy, D. J. (1997) Crystal structure of a Hedgehog autoprocessing domain: homology between Hedgehog and self-splicing proteins. Cell 91, 85-97 . (Pubitemid 27431315)
35. Porter, J. A., von Kessler, D. P., Ekker, S. C., Young, K. E., Lee, J. J., Moses, K., and Beachy, P. A. (1995) The product of hedgehog autoproteolytic cleavage active in local and long-range signalling. Nature 374, 363-366 .
36. Dassa, B., Haviv, H., Amitai, G., and Pietrokovski, S. (2004) Protein splicing and auto-cleavage of bacterial intein-like domains lacking a C′-flanking nucleophilic residue. J. Biol. Chem. 279, 32001-32007 . (Pubitemid 39014644)
37. Aranko, A. S., Oeemig, J. S., and Iwaï, H. (2013) Structural basis for protein trans-splicing by a bacterial intein-like domain: protein ligation without nucleophilic side chains. FEBS J. 280, 3256-3269 .
38. Amitai, G., Belenkiy, O., Dassa, B., Shainskaya, A., and Pietrokovski, S. (2003) Distribution and function of new bacterial intein-like protein domains. Mol. Microbiol. 47, 61-73 . (Pubitemid 36051324)
39. Southworth, M. W., Yin, J., and Perler, F. B. (2004) Rescue of protein splicing activity from a Magnetospirillum magnetotacticum intein-like element. Biochem. Soc. Trans. 32, 250-254 . (Pubitemid 38582101)
40. Volkmann, G., and Mootz, H. D. (2013) Recent Progress in intein research: from mechanism to directed evolution and applications. Cell. Mol. Life Sci. 70, 1185-1206 .
41. Eryilmaz, E., Shah, N. E., Muir, T. W., and Cowburn, D. (2014) Structural and dynamical features of inteins and implications on protein splicing. J. Biol. Chem. 289, 14506-14511 .
42. Romanelli, A., Shekhtman, A., Cowburn, D., and Muir, T. W. (2004) Semisynthesis of a segmental isotopically labeled protein splicing precursor: NMR evidence for an unusual peptide bond at the N-extein-intein junction. Proc. Natl. Acad. Sci. U.S.A. 101, 6397-6402 . (Pubitemid 38585985)
43. Kawasaki, M., Nogami, S., Satow, Y., Ohya, Y., and Anraku, Y. (1997) Identification of three core regions essential for protein splicing of the yeast Vma1 protozyme: a random mutagenesis study of the entire VMA1-derived endonuclease sequence. J. Biol. Chem. 272, 15668-15674 . (Pubitemid 27265537)
44. Chong, S., Williams, K. S., Wotkowicz, C., and Xu, M. Q. (1998) Modulation of protein splicing of the Saccharomyces cerevisiae vacuolar membrane ATPase intein. J. Biol. Chem. 273, 10567-10577 . (Pubitemid 28227668)
45. Amitai, G., Callahan, B. P., Stanger, M. J., Belfort, G., and Belfort, M. (2009) Modulation of intein activity by its neighboring extein substrates. Proc. Natl. Acad. Sci. U.S.A. 106, 11005-11010 .
46. Oeemig, J. S., Zhou, D., Kajander, T., Wlodawer, A., and Iwaï, H. (2012) NMR and crystal structures of the Pyrococcus horikoshii RadA intein guide: a strategy for engineering a highly efficient and promiscuous intein. J. Mol. Biol. 421, 85-99 .
47. Nogami, S., Satow, Y., Ohya, Y., and Anraku, Y. (1997) Probing novel elements for protein splicing in the yeast Vma1 protozyme: a study of replacement mutagenesis and intragenic suppression. Genetics 147, 73-85 . (Pubitemid 27385538)
48. Cheriyan, M., Pedamallu, C. S., Tori, K., and Perler, F. (2013) Faster protein splicing with the Nostoc punctiforme DnaE intein using nonnative extein residues. J. Biol. Chem. 288, 6202-6211 .
49. Shah, N. H., Eryilmaz, E., Cowburn, D., and Muir, T. W. (2013) Extein residues play an intimate role in the rate-limiting step of protein transsplicing. J. Am. Chem. Soc. 135, 5839-5847 .
50. Pearl, E. J., Bokor, A. A., Butler, M. I., Poulter, R. T., and Wilbanks, S. M. (2007) Preceding hydrophobic and β-branched amino acids attenuate splicing by the CnePRP8 intein. Biochim. Biophys. Acta 1774, 995-1001 . (Pubitemid 47176957)
51. Pearl, E. J., Tyndall, J. D., Poulter, R. T., and Wilbanks, S. M. (2007) Sequence requirements for splicing by the Cne PRP8 intein. FEBS Lett. 581, 3000-3004 . (Pubitemid 46899045)
52. Tori, K., and Perler, F. B. (2011) The Arthrobacter species FB24 Arth-1007 (DnaB) intein is a pseudogene. PLoS One 6, e26361 .
53. Tori, K., Cheriyan, M., Pedamallu, C. S., Contreras, M. A., and Perler, F. B. (2012) The Thermococcus kodakaraensis Tko CDC21-1 intein activates its N-terminal splice junction in the absence of a conserved histidine by a compensatory mechanism. Biochemistry 51, 2496-2505 .
54. Poland, B. W., Xu, M. Q., and Quiocho, F. A. (2000) Structural insights into the protein splicing mechanism of PI-SceI. J. Biol. Chem. 275, 16408-16413 . (Pubitemid 30398859)
55. Klabunde, T., Sharma, S., Telenti, A., Jacobs, W. R., Jr., and Sacchettini, J. C. (1998) Crystal structure of GyrA intein from Mycobacterium xenopi reveals structural basis of protein splicing. Nat. Struct. Biol. 5, 31-36 . (Pubitemid 28048974)
56. Mizutani, R., Nogami, S., Kawasaki, M., Ohya, Y., Anraku, Y., and Satow, Y. (2002) Protein-splicing reaction via a thiazolidine intermediate: crystal structure of the VMA1-derived endonuclease bearing the N and C-terminal propeptides. J. Mol. Biol. 316, 919-929 . (Pubitemid 34722131)
57. Ding, Y., Xu, M. Q., Ghosh, I., Chen, X., Ferrandon, S., Lesage, G., and Rao, Z. (2003) Crystal structure of a mini-intein reveals a conserved catalytic module involved in side chain cyclization of asparagine during protein splicing. J. Biol. Chem. 278, 39133-39142 . (Pubitemid 37221816)
58. Dearden, A. K., Callahan, B., Roey, P. V., Li, Z., Kumar, U., Belfort, M., and Nayak, S. K. (2013) A conserved threonine spring-loads precursor for intein splicing. Protein Sci. 22, 557-563 .
59. Du, Z., Zheng, Y., Patterson, M., Liu, Y., and Wang, C. (2011) pKa coupling at the intein active site: implications for the coordination mechanism of protein splicing with a conserved aspartate. J. Am. Chem. Soc. 133, 10275-10282 .
60. Du, Z., Shemella, P. T., Liu, Y., McCallum, S. A., Pereira, B., Nayak, S. K., Belfort, G., Belfort, M., and Wang, C. (2009) Highly conserved histidine plays a dual catalytic role in protein splicing: a pKa shift mechanism. J. Am. Chem. Soc. 131, 11581-11589 .
61. Van Roey, P., Pereira, B., Li, Z., Hiraga, K., Belfort, M., and Derbyshire, V. (2007) Crystallographic and mutational studies of Mycobacterium tuberculosis recA mini-inteins suggest a pivotal role for a highly conserved aspartate residue. J. Mol. Biol. 367, 162-173 . (Pubitemid 46274715)
62. Schwarzer, D., Ludwig, C., Thiel, I. V., and Mootz, H. D. (2012) Probing intein-catalyzed thioester formation by unnatural amino acid substitutions in the active site. Biochemistry 51, 233-242 .
63. Shingledecker, K., Jiang, S. q., and Paulus, H. (2000) Reactivity of the cysteine residues in the protein splicing active center of the Mycobacterium tuberculosis RecA intein. Arch Biochem. Biophys. 375, 138-144 . (Pubitemid 30133631)
64. Pereira, B., Shemella, P. T., Amitai, G., Belfort, G., Nayak, S. K., and Belfort, M. (2011) Spontaneous proton transfer to a conserved intein residue determines on-pathway protein splicing. J. Mol. Biol. 406, 430-442 .
65. Wood, D. W., Wu, W., Belfort, G., Derbyshire, V., and Belfort, M. (1999) A genetic system yields self-cleaving inteins for bioseparations. Nat. Biotechnol. 17, 889-892 . (Pubitemid 29416663)
66. Brennan, T. V., and Clarke, S. (1995) Effect of adjacent histidine and cysteine residues on the spontaneous degradation of asparaginyl-and aspartyl-containing peptides. Int. J. Pept. Protein Res. 45, 547-553 .
67. Mujika, J. I., Lopez, X., and Mulholland, A. J. (2009) Modeling protein splicing: reaction pathway for C-terminal splice and intein scission. J. Phys. Chem. B 113, 5607-5616 .
68. Mujika, J. I., Lopez, X., and Mulholland, A. J. (2012) Mechanism of C-terminal intein cleavage in protein splicing from QM/MM molecular dynamics simulations. Org. Biomol. Chem. 10, 1207-1218 .
69. Frutos, S., Goger, M., Giovani, B., Cowburn, D., and Muir, T. W. (2010) Branched intermediate formation stimulates peptide bond cleavage in protein splicing. Nat. Chem. Biol. 6, 527-533 .
70. Wood, D. W., Derbyshire, V., Wu, W., Chartrain, M., Belfort, M., and Belfort, G. (2000) Optimized single-step affinity purification with a selfcleaving intein applied to human acidic fibroblast growth factor. Biotechnol. Prog. 16, 1055-1063 . (Pubitemid 32044859)
71. Mills, K. V., Dorval, D. M., and Lewandowski, K. T. (2005) Kinetic analysis of the individual steps of protein splicing for the Pyrococcus abyssi PolII intein. J. Biol. Chem. 280, 2714-2720 . (Pubitemid 40189377)
72. Shemella, P., Pereira, B., Zhang, Y., Van Roey, P., Belfort, G., Garde, S., and Nayak, S. K. (2007) Mechanism for intein C-terminal cleavage: a proposal from quantum mechanical calculations. Biophys. J. 92, 847-853 . (Pubitemid 46203214)
73. Shemella, P. T., Topilina, N. I., Soga, I., Pereira, B., Belfort, G., Belfort, M., and Nayak, S. K. (2011) Electronic structure of neighboring extein residue modulates intein C-terminal cleavage activity. Biophys. J. 100, 2217-2225 .
74. Chen, L., Benner, J., and Perler, F. B. (2000) Protein splicing in the absence of an intein penultimate histidine. J. Biol. Chem. 275, 20431-20435 . (Pubitemid 30457620)
75. Wang, S., and Liu, X. Q. (1997) Identification of an unusual intein in chloroplast ClpP protease of Chlamydomonas eugametos. J. Biol. Chem. 272, 11869-11873 . (Pubitemid 27202757)
76. Johnson, M. A., Southworth, M. W., Herrmann, T., Brace, L., Perler, F. B., and Wüthrich, K. (2007)NMRStructure of a KlbA intein precursor from Methanococcus jannaschii. Protein Sci. 16, 1316-1328 . (Pubitemid 46984866)
77. Southworth, M. W., Benner, J., and Perler, F. B. (2000) An alternative protein splicing mechanism for inteins lacking an N-terminal nucleophile. EMBO J. 19, 5019-5026 .
78. Mills, K. V., Manning, J. S., Garcia, A. M., and Wuerdeman, L. A. (2004) Protein splicing of a Pyrococcus abyssi intein with a C-terminal glutamine. J. Biol. Chem. 279, 20685-20691 . (Pubitemid 38656464)
79. Nicastri, M. C., Xega, K., Li, L., Xie, J., Wang, C., Linhardt, R. J., Reitter, J. N., and Mills, K. V. (2013) Internal disulfide bond acts as a switch for intein activity. Biochemistry 52, 5920-5927 .
80. Amitai, G., Dassa, B., and Pietrokovski, S. (2004) Protein splicing of inteins with atypical glutamine and aspartate C-terminal residues. J. Biol. Chem. 279, 3121-3131 . (Pubitemid 38140544)
81. Shao, Y., and Paulus, H. (1997) Protein splicing: estimation of the rate of O-N and S-N acyl rearrangements, the last step of the splicing process. J. Pept. Res. 50, 193-198 . (Pubitemid 27381448)
82. Tori, K., and Perler, F. B. (2011) Expanding the definition of class 3 inteins and their proposed phage origin. J. Bacteriol. 193, 2035-2041 .
83. Brace, L. E., Southworth, M. W., Tori, K., Cushing, M. L., and Perler, F. (2010) The Deinococcus radiodurans Snf2 intein caught in the act: detection of the Class 3 intein signature block F branched intermediate. Protein Sci. 19, 1525-1533.
84. O'Brien, K. M., Schufreider, A. K., McGill, M. A., O'Brien, K. M., Reitter, J. N., and Mills, K. V. (2010) Mechanism of protein splicing of the Pyrococcus abyssi Lon protease intein. Biochem. Biophys. Res. Commun. 403, 457-461 .
85. Volkmann, G., and Liu, X. Q. (2011) Intein lacking conserved C-terminal motif G retains controllable N-cleavage activity. FEBS J. 278, 3431-3446 .
86. Mizutani, R., Anraku, Y., and Satow, Y. (2004) Protein splicing of yeast VMA1-derived endonuclease via thiazolidine intermediates. J. Synchrotron Radiat. 11, 109-112 . (Pubitemid 40085648)
87. Sun, P., Ye, S., Ferrandon, S., Evans, T. C., Xu, M. Q., and 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 . (Pubitemid 41503274)
88. Nichols, N. M., Benner, J. S., Martin, D. D., and Evans, T. C., Jr. (2003) Zinc ion effects on individual Ssp DnaE intein splicing steps: regulating pathway progression. Biochemistry 42, 5301-5311 . (Pubitemid 36560426)
89. Shah, N. H., Dann, G. P., Vila-Perelló, M., Liu, Z., and Muir, T. W. (2012) Ultrafast protein splicing is common among cyanobacterial split inteins: implications for protein engineering. J. Am. Chem. Soc. 134, 11338-11341 .
90. Nichols, N. M., and Evans, T. C., Jr. (2004) Mutational analysis of protein splicing, cleavage, and self-association reactions mediated by the naturally split Ssp DnaE intein. Biochemistry 43, 10265-10276 . (Pubitemid 39030917)
91. Carvajal-Vallejos, P., Pallissé, R., Mootz, H. D., and Schmidt, S. R. (2012) Unprecedented rates and efficiencies revealed for new natural split inteins from metagenomic sources. J. Biol. Chem. 287, 28686-28696 .
92. Saleh, L., Southworth, M. W., Considine, N., O'Neill, C., Benner, J., Bollinger, J. M., Jr., and Perler, F. B. (2011) Branched intermediate formation is the slowest step in the protein splicing reaction of the Ala1 KlbA intein from Methanococcus jannaschii. Biochemistry 50, 10576-10589 .
93. Dalgaard, J. Z., Moser, M. J., Hughey, R., and Mian, I. S. (1997) Statistical modeling, phylogenetic analysis and structure prediction of a protein splicing domain common to inteins and Hedgehog proteins. J. Comput. Biol. 4, 193-214 . (Pubitemid 27318316)
94. Mootz, H. D. (2009) Split inteins as versatile tools for protein semisynthesis. Chembiochem 10, 2579-2589 .
95. Cambon-Bonavita, M. A., Schmitt, P., Zieger, M., Flaman, J. M., Lesongeur, F., Raguénès, G., Bindel, D., Frisch, N., Lakkis, Z., Dupret, D., Barbier, G., and Quérellou, J. (2000) Cloning, expression, and characterization of DNA polymerase I from the hyperthermophilic archaea Thermococcus fumicolans. Extremophiles 4, 215-225 .
96. Ghosh, I., Sun, L., and Xu, M. Q. (2001) Zinc Inhibition of protein transsplicing and identification of regions essential for splicing and association of a split intein. J. Biol. Chem. 276, 24051-24058 .
97. Mills, K. V., and Paulus, H. (2001) Reversible inhibition of protein splicing by zinc ion. J. Biol. Chem. 276, 10832-10838 . (Pubitemid 38089259)
98. Zhang, L., Xiao, N., Pan, Y., Zheng, Y., Pan, Z., Luo, Z., Xu, X., and Liu, Y. (2010) Binding and inhibition of copper ions to RecA inteins from Mycobacterium tuberculosis. Chemistry 16, 4297-4306 .
99. Callahan, B. P., Topilina, N. I., Stanger, M. J., Van Roey, P., and Belfort, M. (2011) Structure of catalytically competent intein caught in a redox trap with functional and evolutionary implications. Nat. Struct. Mol. Biol. 18, 630-633.
100. Chen, W., Li, L., Du, Z., Liu, J., Reitter, J. N., Mills, K. V., Linhardt, R. J., and Wang, C. (2012) Intramolecular disulfide bond between catalytic cysteines in an intein precursor. J. Am. Chem. Soc. 134, 2500-2503 .