Enigmatic Distribution, Evolution, and Function of Inteins*

Inteins are mobile genetic elements capable of self-splicing post-translationally. They exist in all three domains of life including in viruses and bacteriophage, where they have a sporadic distribution even among very closely related species. In this review, we address this anomalous distribution from the point of view of the evolution of the host species as well as the intrinsic features of the inteins that contribute to their genetic mobility. We also discuss the incidence of inteins in functionally important sites of their host proteins. Finally, we describe instances of conditional protein splicing. These latter observations lead us to the hypothesis that some inteins have adapted to become sensors that play regulatory roles within their host protein, to the advantage of the organism in which they reside.

[1]  M. Breitbart,et al.  A bioinformatic analysis of ribonucleotide reductase genes in phage genomes and metagenomes , 2013, BMC Evolutionary Biology.

[2]  Frédéric Partensky,et al.  Accelerated evolution associated with genome reduction in a free-living prokaryote , 2005, Genome Biology.

[3]  K. Mills,et al.  Protein Splicing of a Pyrococcus abyssi Intein with a C-terminal Glutamine* , 2004, Journal of Biological Chemistry.

[4]  J. Antón,et al.  Metatranscriptomic analysis of extremely halophilic viral communities , 2011, The ISME Journal.

[5]  N. Moran,et al.  Lifestyle evolution in symbiotic bacteria: insights from genomics. , 2000, Trends in ecology & evolution.

[6]  J. Querellou,et al.  Cloning, expression, and characterization of DNA polymerase I from the hyperthermophilic archaea Thermococcus fumicolans , 2000, Extremophiles.

[7]  F. Perler,et al.  The mechanism of protein splicing and its modulation by mutation. , 1996, The EMBO journal.

[8]  G. Wagner,et al.  Transposable element recruitments in the mammalian placenta: impacts and mechanisms. , 2012, Briefings in functional genomics.

[9]  G. Fournous,et al.  Phage as agents of lateral gene transfer. , 2003, Current opinion in microbiology.

[10]  S. Džidić,et al.  Horizontal gene transfer-emerging multidrug resistance in hospital bacteria. , 2003, Acta pharmacologica Sinica.

[11]  D. O. Hessen,et al.  Genome streamlining and the elemental costs of growth. , 2010, Trends in ecology & evolution.

[12]  A. Burt,et al.  Recurrent invasion and extinction of a selfish gene. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Davison,et al.  Genetic exchange between bacteria in the environment. , 1999, Plasmid.

[14]  R. Poulter,et al.  Multiple, non-allelic, intein-coding sequences in eukaryotic RNA polymerase genes , 2006, BMC Biology.

[15]  S. Feinstein,et al.  A dominant trifluoperazine resistance gene from Saccharomyces cerevisiae has homology with F0F1 ATP synthase and confers calcium-sensitive growth , 1988, Molecular and cellular biology.

[16]  Lisa A. Fitzgerald,et al.  Sequence and annotation of the 369-kb NY-2A and the 345-kb AR158 viruses that infect Chlorella NC64A. , 2007, Virology.

[17]  H. Mootz,et al.  Recent progress in intein research: from mechanism to directed evolution and applications , 2012, Cellular and Molecular Life Sciences.

[18]  N. Moran,et al.  The process of genome shrinkage in the obligate symbiont Buchnera aphidicola , 2001, Genome Biology.

[19]  J. Gill,et al.  The Caulobacter crescentus phage phiCbK: genomics of a canonical phage , 2012, BMC Genomics.

[20]  G. Cook,et al.  Intracellular pH regulation by Mycobacterium smegmatis and Mycobacterium bovis BCG. , 2001, Microbiology.

[21]  J. Gogarten,et al.  Conservation of intron and intein insertion sites: implications for life histories of parasitic genetic elements , 2009, BMC Evolutionary Biology.

[22]  Niels W. Hanson,et al.  Prevalent genome streamlining and latitudinal divergence of planktonic bacteria in the surface ocean , 2013, Proceedings of the National Academy of Sciences.

[23]  D. Fouts,et al.  Whole genome sequencing and comparative genomic analyses of two Vibrio cholerae O139 Bengal-specific Podoviruses to other N4-like phages reveal extensive genetic diversity , 2013, Virology Journal.

[24]  R. Linhardt,et al.  Intramolecular disulfide bond between catalytic cysteines in an intein precursor. , 2012, Journal of the American Chemical Society.

[25]  V. Lazarevic.  Ribonucleotide reductase genes of Bacillus prophages: a refuge to introns and intein coding sequences. , 2001, Nucleic acids research.

[26]  Tom W Muir,et al.  Protein ligation: an enabling technology for the biophysical analysis of proteins , 2006, Nature Methods.

[27]  Francine B. Perler,et al.  InBase: the Intein Database , 2002, Nucleic Acids Res..

[28]  David W Wood,et al.  Engineering and optimization of an allosteric biosensor protein for peroxisome proliferator-activated receptor γ ligands. , 2011, Biosensors & bioelectronics.

[29]  N. Moran,et al.  Colloquium Papers: Symbiosis as an adaptive process and source of phenotypic complexity , 2007 .

[30]  Robert J Linhardt,et al.  Internal disulfide bond acts as a switch for intein activity. , 2013, Biochemistry.

[31]  R. Sandaa,et al.  Phylogenetic Analysis of Members of the Phycodnaviridae Virus Family, Using Amplified Fragments of the Major Capsid Protein Gene , 2008, Applied and Environmental Microbiology.

[32]  R. Hirata,et al.  Molecular structure of a gene, VMA1, encoding the catalytic subunit of H(+)-translocating adenosine triphosphatase from vacuolar membranes of Saccharomyces cerevisiae. , 1990, The Journal of biological chemistry.

[33]  B. Piégu,et al.  Characteristics of inteins in invertebrate iridoviruses and factors controlling insertion in their viral hosts. , 2013, Molecular phylogenetics and evolution.

[34]  David W. Wood,et al.  A genetic system yields self-cleaving inteins for bioseparations , 1999, Nature Biotechnology.

[35]  Piero Carninci,et al.  Altruistic functions for selfish DNA , 2009, Cell cycle.

[36]  Tom W Muir,et al.  Conditional protein splicing: a new tool to control protein structure and function in vitro and in vivo. , 2003, Journal of the American Chemical Society.

[37]  Z. Hu,et al.  Protein trans-splicing by a split intein encoded in a split DnaE gene of Synechocystis sp. PCC6803. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  F. Perler,et al.  Protein splicing: an analysis of the branched intermediate and its resolution by succinimide formation. , 1994, The EMBO journal.

[39]  J. Andersson,et al.  Lateral gene transfer in eukaryotes , 2005, Cellular and Molecular Life Sciences CMLS.

[40]  Marlene Belfort,et al.  A redox trap to augment the intein toolbox , 2013, Biotechnology and bioengineering.

[41]  M. Belfort.  Bacteriophage introns: parasites within parasites? , 1989, Trends in Genetics.

[42]  H. Paulus,et al.  Inteins as Enzyme , 2001 .

[43]  Curtis A Suttle,et al.  The viriosphere, diversity, and genetic exchange within phage communities. , 2005, Current opinion in microbiology.

[44]  N. Moran,et al.  Deletional bias and the evolution of bacterial genomes. , 2001, Trends in genetics : TIG.

[45]  K. Mills,et al.  Kinetic Analysis of the Individual Steps of Protein Splicing for the Pyrococcus abyssi PolII Intein* , 2005, Journal of Biological Chemistry.

[46]  Alexander Tomasz,et al.  Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole-genome sequencing , 2007, Proceedings of the National Academy of Sciences.

[47]  Georgios Skretas,et al.  Regulation of protein activity with small‐molecule‐controlled inteins , 2005, Protein science : a publication of the Protein Society.

[48]  Olga Zhaxybayeva,et al.  Inteins: structure, function, and evolution. , 2002, Annual review of microbiology.

[49]  Rebecca J. Oakey,et al.  Transposable Elements Re-Wire and Fine-Tune the Transcriptome , 2013, PLoS genetics.

[50]  S. Gribaldo,et al.  The origin and evolution of Archaea: a state of the art , 2006, Philosophical Transactions of the Royal Society B: Biological Sciences.

[51]  T. C. Evans,et al.  Recent advances in protein splicing: manipulating proteins in vitro and in vivo. , 2005, Current opinion in biotechnology.

[52]  P. Keeling.  Functional and ecological impacts of horizontal gene transfer in eukaryotes. , 2009, Current opinion in genetics & development.

[53]  T. Muir,et al.  Protein splicing triggered by a small molecule. , 2002, Journal of the American Chemical Society.

[54]  Christina Toft,et al.  Evolutionary microbial genomics: insights into bacterial host adaptation , 2010, Nature Reviews Genetics.

[55]  Natalya I Topilina,et al.  Recent advances in in vivo applications of intein-mediated protein splicing , 2013, Mobile DNA.

[56]  J. Gogarten,et al.  The Role of Reticulate Evolution in Creating Innovation and Complexity , 2012, International journal of evolutionary biology.

[57]  G. Grover,et al.  Bacterial biosensors for screening isoform-selective ligands for human thyroid receptors α-1 and β-1 , 2012, FEBS open bio.

[58]  J. Claverie,et al.  A new example of viral intein in Mimivirus , 2005, Virology Journal.

[59]  G. Bratbak,et al.  Characterisation of the coccolithovirus intein. , 2011, Marine genomics.

[60]  G. Hatfull.  Mycobacteriophages: genes and genomes. , 2010, Annual review of microbiology.

[61]  G. Steward,et al.  Detection of inteins among diverse DNA polymerase genes of uncultivated members of the Phycodnaviridae , 2009, The ISME Journal.

[62]  Norbert Perrimon,et al.  Temperature-sensitive control of protein activity by conditionally splicing inteins , 2004, Nature Biotechnology.

[63]  Francine B. Perler,et al.  Protein Splicing: How Inteins Escape from Precursor Proteins , 2014, The Journal of Biological Chemistry.

[64]  S. Pietrokovski,et al.  Algal Viruses with Distinct Intraspecies Host Specificities Include Identical Intein Elements , 2005, Applied and Environmental Microbiology.

[65]  M. Belfort,et al.  Genetic definition of a protein-splicing domain: functional mini-inteins support structure predictions and a model for intein evolution. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[66]  A. Janssen,et al.  Acquisition of 1,000 eubacterial genes physiologically transformed a methanogen at the origin of Haloarchaea , 2012, Proceedings of the National Academy of Sciences.

[67]  Gil Amitai,et al.  Protein Splicing of Inteins with Atypical Glutamine and Aspartate C-terminal Residues* , 2004, Journal of Biological Chemistry.

[68]  Tom W Muir,et al.  Inteins: Nature's Gift to Protein Chemists. , 2014, Chemical science.

[69]  H. Paulus,et al.  Protein splicing: characterization of the aminosuccinimide residue at the carboxyl terminus of the excised intervening sequence. , 1995, Biochemistry.

[70]  N. Moran,et al.  Microbial Minimalism Genome Reduction in Bacterial Pathogens , 2002, Cell.

[71]  S. Sedgwick,et al.  Novel structure of the recA locus of Mycobacterium tuberculosis implies processing of the gene product , 1991, Journal of bacteriology.

[72]  Marlene Belfort,et al.  Structure of catalytically competent intein caught in a redox trap with functional and evolutionary implications , 2011, Nature Structural &Molecular Biology.

[73]  Francine B. Perler,et al.  In vitro protein splicing of purified precursor and the identification of a branched intermediate , 1993, Cell.

[74]  G J Olsen,et al.  Compilation and analysis of intein sequences. , 1997, Nucleic acids research.

[75]  S. Ghabrial,et al.  Widespread Horizontal Gene Transfer from Double-Stranded RNA Viruses to Eukaryotic Nuclear Genomes , 2010, Journal of Virology.

[76]  S. Richards,et al.  Widespread Lateral Gene Transfer from Intracellular Bacteria to Multicellular Eukaryotes , 2007, Science.

[77]  X Q Liu,et al.  Protein-splicing intein: Genetic mobility, origin, and evolution. , 2000, Annual review of genetics.

[78]  A. Düsterhöft,et al.  Introns and intein coding sequence in the ribonucleotide reductase genes of Bacillus subtilis temperate bacteriophage SPbeta. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[79]  N. Miyajima,et al.  Sequence analysis of the genome of the unicellular cyanobacterium Synechocystis sp. strain PCC6803. I. Sequence features in the 1 Mb region from map positions 64% to 92% of the genome. , 1995, DNA research : an international journal for rapid publication of reports on genes and genomes.

[80]  S. Pietrokovski.  Intein spread and extinction in evolution. , 2001, Trends in genetics : TIG.

[81]  Jinling Huang,et al.  Horizontal gene transfer in eukaryotes: The weak-link model , 2013, BioEssays : news and reviews in molecular, cellular and developmental biology.

[82]  H Paulus.  Inteins as enzymes. , 2001, Bioorganic chemistry.

[83]  J. Walker,et al.  Distantly related sequences in the alpha‐ and beta‐subunits of ATP synthase, myosin, kinases and other ATP‐requiring enzymes and a common nucleotide binding fold. , 1982, The EMBO journal.

[84]  H. Paulus,et al.  Protein splicing: estimation of the rate of O‐N and S‐N acyl rearrangements, the last step of the splicing process , 2009 .

[85]  S. Ghabrial,et al.  Widespread Horizontal Gene Transfer from Circular Single-stranded DNA Viruses to Eukaryotic Genomes , 2011, BMC Evolutionary Biology.

[86]  Qianqian Li,et al.  Elimination of in vivo cleavage between target protein and intein in the intein-mediated protein purification systems. , 2006, Protein expression and purification.

[87]  P. Kane,et al.  Protein splicing converts the yeast TFP1 gene product to the 69-kD subunit of the vacuolar H(+)-adenosine triphosphatase. , 1990, Science.

[88]  P. Siguier,et al.  I am what I eat and I eat what I am: acquisition of bacterial genes by giant viruses. , 2007, Trends in genetics : TIG.

[89]  P. R. Sibbald,et al.  The P-loop--a common motif in ATP- and GTP-binding proteins. , 1990, Trends in biochemical sciences.

[90]  Shmuel Pietrokovski,et al.  Oriented covalent immobilization of antibodies for measurement of intermolecular binding forces between zipper-like contact surfaces of split inteins. , 2013, Analytical chemistry.

[91]  A. Burt,et al.  Homing endonuclease genes: the rise and fall and rise again of a selfish element. , 2004, Current opinion in genetics & development.

[92]  J. King,et al.  The genome and proteome of a Campylobacter coli bacteriophage vB_CcoM-IBB_35 reveal unusual features , 2012, Virology Journal.

[93]  David R. Liu,et al.  Directed evolution of ligand dependence: small-molecule-activated protein splicing. , 2004, Proceedings of the National Academy of Sciences of the United States of America.