Piwi

The structure of several Piwi and Argonaute proteins (Ago) have been solved. Piwi proteins are RNA-binding proteins with 2 or 3 domains: The N-terminal PAZ domain binds the 3'-end of the guide RNA; the middle MID domain binds the 5'-phosphate of RNA; and the C-terminal PIWI domain acts as an RNase H endonuclease that can cleave RNA.{{Cite journal|last1=Zeng|first1=Lei|last2=Zhang|first2=Qiang|last3=Yan|first3=Kelley|last4=Zhou|first4=Ming-Ming|date=2011-06-01|title=Structural insights into piRNA recognition by the human PIWI-like 1 PAZ domain|journal=Proteins: Structure, Function, and Bioinformatics|language=en|volume=79|issue=6|pages=2004–2009|doi=10.1002/prot.23003|pmid=21465557|issn=1097-0134|pmc=3092821}}{{Cite journal|last1=Wei|first1=Kai-Fa|last2=Wu|first2=Ling-Juan|last3=Chen|first3=Juan|last4=Chen|first4=Yan-feng|last5=Xie|first5=Dao-Xin|date=August 2012|title=Structural evolution and functional diversification analyses of argonaute protein|journal=Journal of Cellular Biochemistry|volume=113|issue=8|pages=2576–2585|doi=10.1002/jcb.24133|issn=1097-4644|pmid=22415963|s2cid=25990631}} The small RNA partners of Ago proteins are microRNAs (miRNAs). Ago proteins utilize miRNAs to silence genes post-transcriptionally or use small-interfering RNAs (siRNAs) in both transcription 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.

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 of piwi-interacting RNA.{{cite journal | vauthors = Tian Y, Simanshu D, Ma J, Patel D| year = 2010 | title = Structural basis for piRNA 2'-O-methylated 3'-end recognition by Piwi PAZ (Piwi/Argonaute/Zwille) domains | journal = Proc. Natl. Acad. Sci. USA | volume = 108 | issue = 3| pages = 903–910 | pmid = 21193640| doi=10.1073/pnas.1017762108| pmc = 3024652| doi-access = free }}

One of the major human homologues, whose upregulation is implicated in the formation of tumours such as seminomas, is called hiwi (for human piwi).{{cite journal | vauthors = Qiao D, Zeeman AM, Deng W, Looijenga LH, Lin H | year = 2002 | title = Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas | journal = Oncogene | volume = 21 | issue = 25| pages = 3988–99 | doi = 10.1038/sj.onc.1205505 | pmid = 12037681 | doi-access = free }}

Homologous proteins in mice have been called miwi (for mouse piwi).{{cite journal | vauthors = Deng W, Lin H | year = 2002 | title = miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis | journal = Dev Cell | volume = 2 | issue = 6| pages = 819–30 | pmid = 12062093 | doi=10.1016/s1534-5807(02)00165-x| doi-access = free }}

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 in Sertoli 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.{{cite journal | vauthors = Mani S, Juliano C| year = 2013 | title = Untangling the Web: The Diverse Functions of the PIWI/piRNA Pathway | journal = Mol. Reprod. Dev. | volume = 80 | issue = 8| pages = 632–664 | pmid = 23712694| doi=10.1002/mrd.22195| pmc = 4234069}}

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 induces heterochromatin formation at centromeres,{{cite journal | vauthors = Thomson T, Lin H| year = 2009 | title = The Biogenesis and Function PIWI Proteins and piRNAs: Progress and Prospect | journal = Annu. Rev. Cell Dev. Biol. | volume = 25 | pages = 355–376 | pmid = 19575643| doi=10.1146/annurev.cellbio.24.110707.175327| pmc = 2780330}} 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.

The piwi domain{{cite journal |vauthors=Cerutti L, Mian N, Bateman A |title=Domains in gene silencing and cell differentiation proteins: the novel PAZ domain and redefinition of the Piwi domain |journal=Trends Biochem. Sci. |volume=25 |issue=10 |pages=481–2 |date=October 2000 |pmid=11050429 |doi= 10.1016/S0968-0004(00)01641-8}} is a protein domain found in piwi proteins and a large number of related nucleic acid-binding proteins, especially those that bind and cleave RNA. The function of the domain is double stranded-RNA-guided hydrolysis of single stranded-RNA that has been determined in the argonaute family of related proteins. Argonautes, the most well-studied family of nucleic-acid binding proteins, are RNase H-like enzymes that carry out the catalytic functions of the RNA-induced silencing complex (RISC). In the well-known cellular process of RNA interference, the argonaute protein in the RISC complex can bind both small interfering RNA (siRNA) generated from exogenous double-stranded RNA and microRNA (miRNA) generated from endogenous non-coding RNA, both produced by the ribonuclease Dicer, to form an RNA-RISC complex. This complex binds and cleaves complementary base pairing messenger RNA, destroying it and preventing its translation into protein. Crystallised piwi domains have a conserved basic binding site for the 5' end of bound RNA; in the case of argonaute proteins binding siRNA strands, the last unpaired nucleotide base of the siRNA is also stabilised by base stacking-interactions between the base and neighbouring tyrosine residues.{{cite journal | vauthors = Ma J, Yuan Y, Meister G, Pei Y, Tuschl T, Patel D | year = 2005 | title = Structural basis for 5'-end-specific recognition of guide RNA by the A. fulgidus Piwi protein | journal = Nature | volume = 434 | issue = 7033| pages = 666–70 | doi = 10.1038/nature03514 | pmid = 15800629 | pmc = 4694588 | bibcode = 2005Natur.434..666M }}

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 early development and morphogenesis of Drosophila melanogaster embryos, in which germ-line maintenance has been extensively studied.{{cite journal | vauthors = Megosh HB, Cox DN, Campbell C, Lin H | year = 2006 | title = The role of PIWI and the miRNA machinery in Drosophila germline determination | journal = Curr Biol | volume = 16 | issue = 19| pages = 1884–94 | doi = 10.1016/j.cub.2006.08.051 | pmid = 16949822 | s2cid = 6397874 | doi-access = free | bibcode = 2006CBio...16.1884M }}

A novel class of longer-than-average miRNAs known as Piwi-interacting RNAs (piRNAs) has been defined in mammalian cells, about 26-31 nucleotides long as compared to the more typical miRNA or siRNA of about 21 nucleotides. These piRNAs are expressed mainly in spermatogenic cells in the testes of mammals.{{cite journal | vauthors = Kim VN | year = 2006 | title = Small RNAs just got bigger: Piwi-interacting RNAs (piRNAs) in mammalian testes | journal = Genes Dev | volume = 20 | issue = 15| pages = 1993–7 | doi = 10.1101/gad.1456106 | pmid = 16882976 | doi-access = free }} 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 the genomes of mice, rats, and humans, with an unusual "clustered" genomic organization{{cite journal | vauthors = Girard A, Sachidanandam R, Hannon GJ, Carmell MA | year = 2006 | title = A germline-specific class of small RNAs binds mammalian Piwi proteins | journal = Nature | volume = 442 | issue = 7099| pages = 199–202 | doi = 10.1038/nature04917 | pmid = 16751776 | bibcode = 2006Natur.442..199G | s2cid = 3185036 }} that may originate from repetitive regions of the genome such as retrotransposons or regions normally organized into heterochromatin, and which are normally derived exclusively from the antisense strand of double-stranded RNA.{{cite journal | vauthors = Vagin VV, Sigova A, Li C, Seitz H, Gvozdev V, Zamore PD | year = 2006 | title = A distinct small RNA pathway silences selfish genetic elements in the germline | journal = Science | volume = 313 | issue = 5785| pages = 320–4 | doi = 10.1126/science.1129333 | pmid = 16809489 | bibcode = 2006Sci...313..320V | s2cid = 40471466 }} piRNAs have thus been classified as repeat-associated small interfering RNAs (rasiRNAs).{{cite journal | vauthors = Saito K, Nishida KM, Mori T, Kawamura Y, Miyoshi K, Nagami T, Siomi H, Siomi MC | year = 2006 | title = Specific association of Piwi with rasiRNAs derived from retrotransposon and heterochromatic regions in the Drosophila genome | journal = Genes Dev | volume = 20 | issue = 16| pages = 2214–22 | doi = 10.1101/gad.1454806 | pmid = 16882972 | pmc=1553205}}

Although their biogenesis is not yet well understood, piRNAs and Piwi proteins are thought to form an endogenous system for silencing the expression of selfish genetic elements such as retrotransposons and thus preventing the gene products of such sequences from interfering with germ cell formation.{{cite journal|vauthors=Ozata DM, Gainetdinov I, Zoch A, Phillip D, Zamore PD|year=2019|title=PIWI-interacting RNAs: small RNAs with big functions|url=https://www.pure.ed.ac.uk/ws/files/78781529/PIWI_interacting_RNAs_AAM_zata_et_al._Revised_v2.3.pdf|journal=Nature Reviews Genetics|volume=20|issue=2|pages=89–108|doi=10.1038/s41576-018-0073-3|pmid=30446728|s2cid=53565676}}

{{notelist|1}}

• {{SCOP|110640}} – Piwi domain in SCOP
• {{PROSITE|PDOC50822}} – Piwi domain in PROSITE
• [https://www.uniprot.org/uniprot/?query=name:piwi+AND+organism:%22Homo+sapiens+%5B9606%5D%22&sort=score UNIPROT Piwi] - Piwi domains

Category:Proteins

Category:Protein domains