Intein


Intein

An intein is a segment of a protein that is able to excise itself and rejoin the remaining portions (the exteins) with a peptide bond. Inteins have also been called "protein introns". [cite journal |author=Anraku Y, Mizutani R, Satow Y |title=Protein splicing: its discovery and structural insight into novel chemical mechanisms |journal=IUBMB Life |volume=57 |issue=8 |pages=563–74 |year=2005 |pmid=16118114 |doi=10.1080/15216540500215499]

Most reported inteins also contain an endonuclease domain that plays a role in intein propagation. In fact, many genes have unrelated intein-coding segments inserted at different positions. For these and other reasons, inteins (or more properly, the gene segments coding for inteins) are sometimes called "selfish genetic elements" butit may be more accurate to call them parasitic. The difference is that "selfish genes" are "selfish" only insofar as to compete with other genes or alleles, but still fulfill a beneficial function for the organism as a whole, whereas "parasitic genes" are functionless.

Intein-mediated protein splicing occurs after mRNA has been translated into a protein. This precursor protein contains three segments - an N-extein followed by the intein followed by a C-extein.After splicing has taken place, the result is also called an extein.

The first intein was discovered in 1987. Since then, inteins have been found in all three domains of life (eukaryotes, bacteria, and archaea). Knowledge regarding the evolutionary situation of inteins and related elements is reviewed in Gogarten & Hilario (2006).The mechanism for the splicing effect is a naturally occurring analogy to the technique for chemically generating medium-sized proteins called native chemical ligation, which was developed at the same time as inteins were discovered.

Inteins in biotechnology

Inteins are very efficient at protein splicing and they have accordingly found an important role in biotechnology. There are more than 200 inteins identified to date, sizes range from 100-800 aa. Inteins have been engineered for particular applications such as protein synthesis, [cite journal |author=Schwarzer D, Cole PA |title=Protein semisynthesis and expressed protein ligation: chasing a protein's tail |journal=Curr Opin Chem Biol |volume=9 |issue=6 |pages=561–9 |year=2005 |pmid=16226484 |doi=10.1016/j.cbpa.2005.09.018] and the selective labeling of protein segments, which is useful for NMR studies of large proteins. [cite journal |author=Muralidharan V, Muir TW |title=Protein ligation: an enabling technology for the biophysical analysis of proteins |journal=Nat. Methods |volume=3 |issue=6 |pages=429–38 |year=2006 |pmid=16721376 |doi=10.1038/nmeth886]

Pharmaceutical inhibition of intein excision may be a useful tool for drug development, the protein that contains the intein will not carry out its normal function if the intein does not excise since its structure will be disrupted.

It has been suggested that inteins could prove useful for achieving allotopic expression of certain highly hydrophobic proteins normally encoded by the mitochondrial genome, for example in gene therapy (de Grey 2000). The hydrophobicity of these proteins is an obstacle to their import into mitochondria. Therefore, the insertion of a non-hydrophobic intein may allow this import to proceed. Excision of the intein after import would then restore the protein to wild-type.

Intein naming conventions

The first part of an intein name is based on the scientific name of the organism in which it is found, and the second part is based on the name of the corresponding gene or extein. For example, the intein found in "Thermoplasma acidophilum" and associated with 'Vacuolar ATPase subunit A' (VMA) is called 'Tac VMA'.

Normally, as in this example, just three letters suffice to specify the organism, but there are variations. For example, additional letters may be added to indicate a strain.If more than one intein is encoded in the corresponding gene, the inteins are given a numerical suffix starting from 5' to 3' or in order of their identification. For example, "Msm dnaB-1".

The segment of the gene that encodes the intein is usually given the same name as the intein, but to avoid confusion, the name of the intein proper is usually capitalized (e.g. Pfu RIR1-1), whereas the name of the corresponding gene segment is italicized.

Full and mini inteins

Inteins can contain a homing endonuclease gene domain in addition to the splicing domains. This domain is responsible for the spread of the intein by cleaving DNA at an intein free allele on the homologous chromosome, triggering the DNA double-stranded break repair (DSBR) system, which then repairs the break, thus copying the intein into a previously intein free site. The HEG domain is not necessary for intein splicing, and so it can be lost, forming a minimal, or mini intein. Several studies have demonstrated the modular nature of inteins by adding or removing HEG domains and determining the activity of the new construct.

Split inteins

Sometimes, the intein of the precursor protein comes from two genes. In this case, the intein is said to be a split intein. For example, in Cyanobacteria, DnaE, the catalytic subunit alpha of DNA polymerase III, is encoded by two separate genes, dnaE-n and dnaE-c. The dnaE-n product consists of an N-extein sequence followed by a 123-aa (amino acid) intein sequence, whereas the dnaE-c product consists of a 36-aa intein sequence followed by a C-extein sequence.

References

* de Grey, Aubrey D. N. J. (2000): Mitochondrial gene therapy: an arena for the biomedical use of inteins. "Trends in Biotechnology" 18(9): 394-399 DOI|10.1016/S0167-7799(00)01476-1 (HTML abstract)

* Gogarten, J. Peter & Hilario, Elena (2006): Inteins, introns, and homing endonucleases: recent revelations about the life cycle of parasitic genetic elements. "BMC Evolutionary Biology" 6: 94 DOI|10.1186/1471-2148-6-94 [http://www.biomedcentral.com/content/pdf/1471-2148-6-94.pdf PDF fulltext]

External links

* [http://www.neb.com/neb/inteins.html The Intein Database]
* [http://bioinformatics.weizmann.ac.il/~pietro/inteins/ Shmuel Pietrokovski's Intein database]


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