| Piwi domain | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
 Structure of thePyrococcus furiosus Argonaute protein.[1] | |||||||||||
| Identifiers | |||||||||||
| Symbol | Piwi | ||||||||||
| Pfam | PF02171 | ||||||||||
| InterPro | IPR003165 | ||||||||||
| PROSITE | PS50822 | ||||||||||
| CDD | cd02826 | ||||||||||
| |||||||||||
Piwi (orPIWI)genes were identified asregulatoryproteins responsible forstem cell andgerm celldifferentiation.[4] Piwi is an abbreviation ofP-elementInducedWImpy testis[a] inDrosophila.[6] Piwi proteins are highlyconservedRNA-binding proteins and are present in both plants and animals.[7] Piwi proteins belong to theArgonaute/Piwi family and have been classified as nuclear proteins. Studies onDrosophila have also indicated that Piwi proteins have no slicer activity conferred by the presence of the Piwi domain.[8] In addition, Piwi associates withheterochromatin protein 1, an epigenetic modifier, and piRNA-complementary sequences. These are indications of the role Piwi plays in epigenetic regulation. Piwi proteins are also thought to control the biogenesis of piRNA as many Piwi-like proteins contain slicer activity which would allow Piwi proteins to process precursor piRNA into mature piRNA.
The structure of several Piwi andArgonaute proteins (Ago) have been solved. Piwi proteins are RNA-binding proteins with 2 or 3domains: The N-terminalPAZ domain binds the 3'-end of the guide RNA; the middleMID domain binds the 5'-phosphate of RNA; and the C-terminalPIWI domain acts as anRNase Hendonuclease that can cleave RNA.[9][10] The small RNA partners of Ago proteins aremicroRNAs (miRNAs). Ago proteins utilize miRNAs to silence genes post-transcriptionally or usesmall-interfering RNAs (siRNAs) in bothtranscription and post-transcription silencing mechanisms. Piwi proteins interact with piRNAs (28–33 nucleotides) that are longer than miRNAs and siRNAs (~20 nucleotides), suggesting that their functions are distinct from those of Ago proteins.[9]
Presently there are four known human Piwi proteins—PIWI-like protein 1, PIWI-like protein 2, PIWI-like protein 3 and PIWI-like protein 4. Human Piwi proteins all contain two RNA binding domains, PAZ and Piwi. The four PIWI-like proteins have a spacious binding site within the PAZ domain which allows them to bind the bulky 2’-OCH3 at the 3’ end ofpiwi-interacting RNA.[11]
One of the major humanhomologues, whose upregulation is implicated in the formation oftumours such asseminomas, is calledhiwi (forhuman piwi).[12]
Homologous proteins in mice have been called miwi (formouse piwi).[13]
PIWI proteins play a crucial role in fertility and germline development across animals and ciliates. Recently identified as a polar granule component, PIWI proteins appear to control germ cell formation so much so that in the absence of PIWI proteins there is a significant decrease in germ cell formation. Similar observations were made with the mouse homologs of PIWI, MILI, MIWI and MIWI2. These homologs are known to be present in spermatogenesis. Miwi is expressed in various stages of spermatocyte formation and spermatid elongation where Miwi2 is expressed inSertoli cells. Mice deficient in either Mili or Miwi-2 have experienced spermatogenic stem cell arrest and those lacking Miwi-2 underwent a degradation of spermatogonia.[14]The effects of piwi proteins in human and mouse germlines seems to stem from their involvement in translation control as Piwi and the small noncoding RNA, piwi-interacting RNA (piRNA), have been known to co-fractionate polysomes. The piwi-piRNA pathway also inducesheterochromatin formation atcentromeres,[15] thus affecting transcription. The piwi-piRNA pathway also appears to protect the genome. First observed in Drosophila, mutant piwi-piRNA pathways led to a direct increase in dsDNA breaks in ovarian germ cells. The role of the piwi-piRNA pathway in transposon silencing may be responsible for the reduction in dsDNA breaks in germ cells.
Thepiwi domain[16] is aprotein domain found in piwi proteins and a large number of relatednucleic acid-binding proteins, especially those that bind and cleaveRNA. The function of the domain isdouble stranded-RNA-guided hydrolysis of single stranded-RNA that has been determined in theargonaute family of related proteins.[1] Argonautes, the most well-studied family of nucleic-acid binding proteins, areRNase H-likeenzymes that carry out thecatalytic functions of theRNA-induced silencing complex (RISC). In the well-known cellular process ofRNA interference, the argonaute protein in the RISC complex can bind bothsmall interfering RNA (siRNA) generated fromexogenous double-stranded RNA andmicroRNA (miRNA) generated fromendogenousnon-coding RNA, both produced by theribonucleaseDicer, to form an RNA-RISC complex. This complex binds and cleavescomplementarybase pairingmessenger RNA, destroying it and preventing itstranslation into protein. Crystallised piwi domains have a conservedbasicbinding site for the5' end of bound RNA; in the case of argonaute proteins binding siRNA strands, the last unpairednucleotide base of the siRNA is also stabilised bybase stacking-interactions between the base and neighbouringtyrosine residues.[17]
Recent evidence suggests that the functional role of piwi proteins in germ-line determination is due to their capacity to interact with miRNAs. Components of the miRNA pathway appear to be present in pole plasm and to play a key role in earlydevelopment andmorphogenesis ofDrosophila melanogasterembryos, in which germ-line maintenance has been extensively studied.[18]
A novel class of longer-than-average miRNAs known asPiwi-interacting RNAs (piRNAs) has been defined inmammalian cells, about 26-31nucleotides long as compared to the more typical miRNA or siRNA of about 21 nucleotides. These piRNAs are expressed mainly inspermatogenic cells in thetestes of mammals.[19] But studies have reported that piRNA expression can be found in the ovarian somatic cells and neuron cells in invertebrates, as well as in many other mammalian somatic cells. piRNAs have been identified in thegenomes ofmice,rats, andhumans, with an unusual "clustered" genomic organization[20] that may originate from repetitive regions of the genome such asretrotransposons or regions normally organized intoheterochromatin, and which are normally derived exclusively from theantisense strand of double-stranded RNA.[21] piRNAs have thus been classified asrepeat-associated small interfering RNAs (rasiRNAs).[22]
Although their biogenesis is not yet well understood, piRNAs and Piwi proteins are thought to form an endogenous system for silencing the expression ofselfish genetic elements such as retrotransposons and thus preventing the gene products of such sequences from interfering with germ cell formation.[21][23]
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