PIWI proteins

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Left: A complete Argonaut protein from the Archaea species Pyrococcus furiosus . Right: The PIWI domain of an Argonaut protein together with a dsRNA . The RNA-protein interaction between the 5 'end of the dsRNA and the tyrosine residue is highlighted in light blue. The magnesium ion is shown as a gray sphere.

The group of piwi - genes encoding a class of proteins associated with piRNAs interact and with the aid of the gene regulation involved in eukaryotes. The name piwi (sometimes also PIWI) stands for P-element induced wimpy testis .

To stop the expression of genes ( gene silencing ) there is a widespread genetic mechanism ( RNA interference ), which consists of binding short RNA fragments that can recognize the corresponding mRNA to proteins (RNases or endonucleases) that break down this mRNA. The special endonucleases have to interact with so-called argonaut proteins. A subgroup of these Argonaut proteins are the Piwi proteins, which are characterized by a certain sequence motif, the Piwi domain.

The peculiarity of the Piwi proteins is that they are only expressed in germ cells and are therefore essential for their development. In Drosophila , mutations in the gene for the Piwi protein lead to sterility and the loss of germ cells in both sexes. Piwi proteins bind to a special group of small RNA fragments, the piRNAs , to interrupt the protein production of their target genes . By examining and characterizing the pi-RNAs, various Piwi proteins have so far been detected.

Research history

Binding domain of a PIWI protein (gray) in complex with siRNA (red)

The Piwi genes were first described in the fruit fly Drosophila . The Piwis are members of a group of genes that were discovered during studies of stem cells and are responsible for regulating the rate of division of germ cells. The Piwi proteins are evolutionarily highly conserved and occur in plants and animals. In humans there is a homolog whose dysregulation is involved in the development of seminomas and is called a Hiwi. The mouse homolog is therefore called Miwi.

Role in RNA interference

The so-called Piwi domain is a protein domain with a sequence homology to the Piwi protein that occurs in a large number of nucleic acid-binding proteins, in particular those that digest RNA. The best studied group of these proteins are the Argonaut proteins. The Argonauts are RNase H -like enzymes that break down RNA in the RISC complex. In RNA interference, the Argonauts in the RISC complex bind to small RNA molecules, the siRNA , which is derived from dsRNA or miRNA . This RNA-protein structure is now able to bind specifically to certain mRNAs , break them down and thus stop the expression of the corresponding genes. From X-ray structure analyzes of crystallized Piwi domains it is known that these have a basic binding site for the 5 'end of the short RNA molecules bound to them. In the case of the Argonauts, this binding occurs with the help of a tyrosine residue.

piRNAs and transposon silencing

It is believed that Piwi proteins their ability to induce germ cell induction of interaction with miRNAs owe, for its key role in the embryonic development of Drosophila are known. A group of short RNAs was discovered that are slightly longer than miRNAs and are called pi-RNAs because of their interaction with the Piwi proteins "Piwi-interacting RNAs" . Their size varies between 26 and 31 nucleotides . These piRNAs are produced exclusively in the spermatogenic cells of the testes . piRNAs have been found in mice , rats and humans. The genes associated with them show an unusual "clustered" genomic organization. which probably originates from repetitive genome sections. Such repetitive DNA sequences are mostly coming from the heterochromatin located retrotransposons , which in turn originated in the antisense strand of the dsRNA have. Due to this fact, piRNAs are also included in the group of repeat-associated small interfering RNAs , the rasiRNAs. Although their biological function is not yet fully understood, it is assumed that piRNAs and Piwi proteins form a molecular system that control the expression of so-called selfish genes such as retrotransposons and thus prevent their disruptive influence on germ cell maturation.

Individual evidence

  1. ↑ CR Fähnle, L. Joshua-Tor: Argonautes confront new small RNAs. In: Curr Opin Chem Biol. 11 (5), Oct 2007, pp. 569-577. Review. PMID 17928262 .
  2. ↑ a b K. Saito, KM Nishida, T. Mori, Y. Kawamura, K. Miyoshi, T. Nagami, H. Siomi, MC Siomi: Specific association of Piwi with rasiRNAs derived from retrotransposon and heterochromatic regions in the Drosophila genome. In: Genes Dev. 20 (16), 2006, pp. 2214-2222. PMID 16882972
  3. ↑ DN Cox, A. Chao, H. Lin: piwi encodes a nucleoplasmic factor whose activity modulates the number and division rate of germline stem cells. In: Development. 127 (3), 2000, pp. 503-514. PMID 10631171
  4. ↑ DN Cox, A. Chao, J. Baker, L. Chang, D. Qiao, H. Lin: A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal. In: Genes Dev. 12 (23), 1998, pp. 3715-3727. PMID 9851978
  5. ^ D. Qiao, AM Zeeman, W. Deng, LH Looijenga, H. Lin: Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas. In: Oncogene . 21 (25), 2002, pp. 3988-3999. PMID 12037681
  6. ^ W. Deng, H. Lin: miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. In: Dev Cell. 2 (6), 2002, pp. 819-830. PMID 12062093
  7. ↑ J. Ma, Y. Yuan, G. Meister, Y. Pei, T. Tuschl, D. Patel: Structural basis for 5'-end-specific recognition of guide RNA by the A. fulgidus Piwi protein. In: Nature. 434 (7033), 2005, pp. 666-670. PMID 15800629
  8. ↑ HB Megosh, DN Cox, C. Campbell, H. Lin: The role of PIWI and the miRNA machinery in Drosophila germline determination. In: Curr Biol. 16 (19), 2006, pp. 1884-1894. PMID 16949822
  9. ↑ VN Kim: Small RNAs just got bigger: Piwi-interacting RNAs (piRNAs) in mammalian testes. In: Genes Dev. 20 (15), 2006, pp. 1993-1997. PMID 16882976
  10. ↑ A. Girard, R. Sachidanandam, GJ Hannon, MA Carmell: A germline-specific class of small RNAs binds mammalian Piwi proteins. In: Nature. 442 (7099), 2006, pp. 199-202. PMID 16751776
  11. ↑ a b V. V. Vagin, A. Sigova, C. Li, H. Seitz, V. Gvozdev, Zamore PD: A distinct small RNA silences pathway selfish genetic elements in the germline. In: Science. 313 (5785), 2006, pp. 320-324. PMID 16809489

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