Piwi

Last updated
Piwi domain
PDB 1z26 EBI.jpg
Structure of the Pyrococcus furiosus Argonaute protein. [1]
Identifiers
SymbolPiwi
Pfam PF02171
InterPro IPR003165
PROSITE PS50822
CDD cd02826
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1u04 ​, 1w9h ​, 1ytu ​, 1yvu ​, 1z25 ​, 1z26 ​, 2bgg ​, 2f8s ​, 2f8t ​, 2nub ​, 2w42 ​
The piwi domain of an argonaute protein with bound siRNA, components of the RNA-induced silencing complex that mediates gene silencing by RNA interference. 1ytu argonaute dsrna.png
The piwi domain of an argonaute protein with bound siRNA, components of the RNA-induced silencing complex that mediates gene silencing by RNA interference.
All human Piwi proteins and argonaute proteins have the same RNA binding domains, PAZ and Piwi. Piwi.PNG
All human Piwi proteins and argonaute proteins have the same RNA binding domains, PAZ and Piwi.
Piwi-piRNA interactions: Within the nucleus, this pathway is involved in DNA methylation (A), histone methylation of H3K9 through interactions with heterochromatin protein 1 (HP1) and H3K9 histone methyltransferase (B). The Piwi-piRNA pathway also interacts with the elF translational initiator (C). Piwi-piRNA pathway1.png
Piwi-piRNA interactions: Within the nucleus, this pathway is involved in DNA methylation (A), histone methylation of H3K9 through interactions with heterochromatin protein 1 (HP1) and H3K9 histone methyltransferase (B). The Piwi-piRNA pathway also interacts with the elF translational initiator (C).

Piwi (or PIWI) genes were identified as regulatory proteins responsible for stem cell and germ cell differentiation. [4] Piwi is an abbreviation of P-element Induced WImpy testis [lower-alpha 1] in Drosophila . [6] Piwi proteins are highly conserved RNA-binding proteins and are present in both plants and animals. [7] Piwi proteins belong to the Argonaute/Piwi family and have been classified as nuclear proteins. Studies on Drosophila have also indicated that Piwi proteins have no slicer activity conferred by the presence of the Piwi domain. [8] In addition, Piwi associates with heterochromatin 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.

Contents

Protein structure and function

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. [9] [10] 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. [9]

Human Piwi 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. [11]

One of the major human homologues, whose upregulation is implicated in the formation of tumours such as seminomas, is called hiwi (for human piwi). [12]

Homologous proteins in mice have been called miwi (for mouse piwi). [13]

Role in germline cells

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. [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 induces heterochromatin formation at centromeres, [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.

Role in RNA interference

The piwi domain [16] 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. [1] 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. [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 early development and morphogenesis of Drosophila melanogaster embryos, in which germ-line maintenance has been extensively studied. [18]

piRNAs and transposon silencing

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. [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 the genomes of mice, rats, and humans, with an unusual "clustered" genomic organization [20] 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. [21] piRNAs have thus been classified as repeat-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 of selfish genetic elements such as retrotransposons and thus preventing the gene products of such sequences from interfering with germ cell formation. [21] [23]

Footnotes

  1. ↑ The word Wimpy itself comes from White color of eyes and Impotency [or profound infertility]. Y is added as a suffix to form a more pronounceable and coherent word. [5]

Related Research Articles

<span class="mw-page-title-main">Dicer</span> Enzyme that cleaves double-stranded RNA (dsRNA) into short dsRNA fragments

Dicer, also known as endoribonuclease Dicer or helicase with RNase motif, is an enzyme that in humans is encoded by the DICER1 gene. Being part of the RNase III family, Dicer cleaves double-stranded RNA (dsRNA) and pre-microRNA (pre-miRNA) into short double-stranded RNA fragments called small interfering RNA and microRNA, respectively. These fragments are approximately 20–25 base pairs long with a two-base overhang on the 3′-end. Dicer facilitates the activation of the RNA-induced silencing complex (RISC), which is essential for RNA interference. RISC has a catalytic component Argonaute, which is an endonuclease capable of degrading messenger RNA (mRNA).

The RNA-induced silencing complex, or RISC, is a multiprotein complex, specifically a ribonucleoprotein, which functions in gene silencing via a variety of pathways at the transcriptional and translational levels. Using single-stranded RNA (ssRNA) fragments, such as microRNA (miRNA), or double-stranded small interfering RNA (siRNA), the complex functions as a key tool in gene regulation. The single strand of RNA acts as a template for RISC to recognize complementary messenger RNA (mRNA) transcript. Once found, one of the proteins in RISC, Argonaute, activates and cleaves the mRNA. This process is called RNA interference (RNAi) and it is found in many eukaryotes; it is a key process in defense against viral infections, as it is triggered by the presence of double-stranded RNA (dsRNA).

<span class="mw-page-title-main">Argonaute</span> Protein that plays a role in RNA silencing process

The Argonaute protein family, first discovered for its evolutionarily conserved stem cell function, plays a central role in RNA silencing processes as essential components of the RNA-induced silencing complex (RISC). RISC is responsible for the gene silencing phenomenon known as RNA interference (RNAi). Argonaute proteins bind different classes of small non-coding RNAs, including microRNAs (miRNAs), small interfering RNAs (siRNAs) and Piwi-interacting RNAs (piRNAs). Small RNAs guide Argonaute proteins to their specific targets through sequence complementarity, which then leads to mRNA cleavage, translation inhibition, and/or the initiation of mRNA decay.

Piwi-interacting RNA (piRNA) is the largest class of small non-coding RNA molecules expressed in animal cells. piRNAs form RNA-protein complexes through interactions with piwi-subfamily Argonaute proteins. These piRNA complexes are mostly involved in the epigenetic and post-transcriptional silencing of transposable elements and other spurious or repeat-derived transcripts, but can also be involved in the regulation of other genetic elements in germ line cells.

RNA-induced transcriptional silencing (RITS) is a form of RNA interference by which short RNA molecules – such as small interfering RNA (siRNA) – trigger the downregulation of transcription of a particular gene or genomic region. This is usually accomplished by posttranslational modification of histone tails which target the genomic region for heterochromatin formation. The protein complex that binds to siRNAs and interacts with the methylated lysine 9 residue of histones H3 (H3K9me2) is the RITS complex.

RNA silencing or RNA interference refers to a family of gene silencing effects by which gene expression is negatively regulated by non-coding RNAs such as microRNAs. RNA silencing may also be defined as sequence-specific regulation of gene expression triggered by double-stranded RNA (dsRNA). RNA silencing mechanisms are conserved among most eukaryotes. The most common and well-studied example is RNA interference (RNAi), in which endogenously expressed microRNA (miRNA) or exogenously derived small interfering RNA (siRNA) induces the degradation of complementary messenger RNA. Other classes of small RNA have been identified, including piwi-interacting RNA (piRNA) and its subspecies repeat associated small interfering RNA (rasiRNA).

oskar is a gene required for the development of the Drosophila embryo. It defines the posterior pole during early embryogenesis. Its two isoforms, short and long, play different roles in Drosophila embryonic development. oskar was named after the main character from the Günter Grass novel The Tin Drum, who refuses to grow up.

<span class="mw-page-title-main">EIF2C2</span> Protein-coding gene in the species Homo sapiens

Protein argonaute-2 is a protein that in humans is encoded by the EIF2C2 gene.

<span class="mw-page-title-main">EIF2C1</span> Protein-coding gene in the species Homo sapiens

Protein argonaute-1 is a protein that in humans is encoded by the EIF2C1 gene.

<span class="mw-page-title-main">PIWIL1</span> Protein-coding gene in the species Homo sapiens

Piwi-like protein 1 is a protein that in humans is encoded by the PIWIL1 gene.

<span class="mw-page-title-main">Tudor domain</span>

In molecular biology, a Tudor domain is a conserved protein structural domain originally identified in the Tudor protein encoded in Drosophila. The Tudor gene was found in a Drosophila screen for maternal factors that regulate embryonic development or fertility. Mutations here are lethal for offspring, inspiring the name Tudor, as a reference to the Tudor King Henry VIII and the several miscarriages experienced by his wives.

Nuage are Drosophila melanogaster germline granules. Nuage are the hallmark of Drosophila melanogaster germline cells, which have an electron-dense perinuclear structure and can silence the selfish genetic elements in Drosophila melanogaster. The term 'Nuage' comes from the French word for 'cloud', as they appear as nebulous electron-dense bodies by electron microscopy. They are found in nurse cells of the developing Drosophila melanogaster egg chamber and are composed of various types of proteins, including RNA-helicases, Tudor domain proteins, Piwi-clade Argonaute proteins, in addition to a PRMT5 methylosome composed of Capsuléen and its co-factor, Valois (MEP50).

Vasa is an RNA binding protein with an ATP-dependent RNA helicase that is a member of the DEAD box family of proteins. The vasa gene is essential for germ cell development and was first identified in Drosophila melanogaster, but has since been found to be conserved in a variety of vertebrates and invertebrates including humans. The Vasa protein is found primarily in germ cells in embryos and adults, where it is involved in germ cell determination and function, as well as in multipotent stem cells, where its exact function is unknown.

The RNA-binding Proteins Database (RBPDB) is a biological database of RNA-binding protein specificities that includes experimental observations of RNA-binding sites. The experimental results included are both in vitro and in vivo from primary literature. It includes four metazoan species, which are Homo sapiens, Mus musculus, Drosophila melanogaster, and Caenorhabditis elegans. RNA-binding domains included in this database are RNA recognition motif, K homology, CCCH zinc finger, and more domains. As of 2021, the latest RBPDB release includes 1,171 RNA-binding proteins.

Transposon silencing is a form of transcriptional gene silencing targeting transposons. Transcriptional gene silencing is a product of histone modifications that prevent the transcription of a particular area of DNA. Transcriptional silencing of transposons is crucial to the maintenance of a genome. The “jumping” of transposons generates genomic instability and can cause extremely deleterious mutations. Transposable element insertions have been linked to many diseases including hemophilia, severe combined immunodeficiency, and predisposition to cancer. The silencing of transposons is therefore extremely critical in the germline in order to stop transposon mutations from developing and being passed on to the next generation. Additionally, these epigenetic defenses against transposons can be heritable. Studies in Drosophila, Arabidopsis thaliana, and mice all indicate that small interfering RNAs are responsible for transposon silencing. In animals, these siRNAS and piRNAs are most active in the gonads.

RDE-1 (RNAi-DEfective 1) is a primary Argonaute protein required for RNA-mediated interference (RNAi) in Caenorhabditis elegans. The rde-1 gene locus was first characterized in C. elegans mutants resistant to RNAi, and is a member of a highly conserved Piwi gene family that includes plant, Drosophila, and vertebrate homologs.

The gene Maelstrom, Mael, creates a protein, which was first located in Drosophila melanogaster in the nuage perinuclear structure and has functionality analogous to the spindle, spn, gene class. Its mammalian homolog is MAEL.

<span class="mw-page-title-main">Piwi like rna-mediated gene silencing 4</span> Protein-coding gene in the species Homo sapiens

Piwi like RNA-mediated gene silencing 4 is a protein that in humans is encoded by the PIWIL4 gene.

piwi-interacting RNA (piRNA) belongs to the small RNA class found in eukaryotic organisms, their major role is to regulate the expression of genes by the mRNA degradation or silencing. After the association with argonaute protein family, these short RNA guide the RNA-induced silencing complex (RISC) to their target by sequence complementarity. piRNAs have approximately from 26 to 31 nucleotides and are found in almost all metazoans.

Haifan Lin is a Chinese-born American stem cell biologist. He is the Eugene Higgins Chair Professor of Cell Biology at Yale University and the founding Director of the Yale Stem Cell Center. He previously founded and directed the Stem Cell Research Program at Duke University. Recognized for his significant contributions to stem cell research, he was elected to the US National Academy of Sciences and American Academy of Arts and Sciences in 2018.

References

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  2. ↑ "Uniprot: The Universal knowledge database". Nucleic Acids Research. 45 (D1): D158–D169. 2017. doi:10.1093/nar/gkw1099. PMC   5210571 . PMID   27899622.
  3. ↑ Lindse K (2013). "Piwi-RNAs, the Defenders of the Genome".{{cite journal}}: Cite journal requires |journal= (help)
  4. ↑ Cox DN, Chao A, Lin H (2000). "piwi encodes a nucleoplasmic factor whose activity modulates the number and division rate of germline stem cells". Development. 127 (3): 503–14. doi:10.1242/dev.127.3.503. PMID   10631171.
  5. ↑ Ross RJ, Weiner MM, Lin H (2014). "PIWI proteins and PIWI-interacting RNAs in the soma". Nature. 505 (7483): 353–359. doi: 10.1038/nature12987 . PMC   4265809 . PMID   24429634.
  6. ↑ Lin H, Spradling AC (1997). "A novel group of pumilio mutations affects the asymmetric division of germline stem cells in the Drosophila ovary". Development. 124 (12): 2463–2476. doi:10.1242/dev.124.12.2463. PMID   9199372.
  7. ↑ Cox DN, Chao A, Baker J, Chang L, Qiao D, Lin H (1998). "A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal". Genes Dev. 12 (23): 3715–27. doi:10.1101/gad.12.23.3715. PMC   317255 . PMID   9851978.
  8. ↑ Darricarrere N, Liu N, Watanabe T, Lin H (2013). "Function of Piwi, a nuclear Piwi/Argonaute protein, is independent of its slicer activity". Proc Natl Acad Sci USA. 110 (6): 1297–1302. Bibcode:2013PNAS..110.1297D. doi: 10.1073/pnas.1213283110 . PMC   3557079 . PMID   23297219.
  9. 1 2 Zeng, Lei; Zhang, Qiang; Yan, Kelley; Zhou, Ming-Ming (2011-06-01). "Structural insights into piRNA recognition by the human PIWI-like 1 PAZ domain". Proteins: Structure, Function, and Bioinformatics. 79 (6): 2004–2009. doi:10.1002/prot.23003. ISSN   1097-0134. PMC   3092821 . PMID   21465557.
  10. ↑ Wei, Kai-Fa; Wu, Ling-Juan; Chen, Juan; Chen, Yan-feng; Xie, Dao-Xin (August 2012). "Structural evolution and functional diversification analyses of argonaute protein". Journal of Cellular Biochemistry. 113 (8): 2576–2585. doi:10.1002/jcb.24133. ISSN   1097-4644. PMID   22415963. S2CID   25990631.
  11. ↑ Tian Y, Simanshu D, Ma J, Patel D (2010). "Structural basis for piRNA 2'-O-methylated 3'-end recognition by Piwi PAZ (Piwi/Argonaute/Zwille) domains". Proc. Natl. Acad. Sci. USA. 108 (3): 903–910. doi: 10.1073/pnas.1017762108 . PMC   3024652 . PMID   21193640.
  12. ↑ Qiao D, Zeeman AM, Deng W, Looijenga LH, Lin H (2002). "Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas". Oncogene. 21 (25): 3988–99. doi: 10.1038/sj.onc.1205505 . PMID   12037681.
  13. ↑ Deng W, Lin H (2002). "miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis". Dev Cell. 2 (6): 819–30. doi: 10.1016/s1534-5807(02)00165-x . PMID   12062093.
  14. ↑ Mani S, Juliano C (2013). "Untangling the Web: The Diverse Functions of the PIWI/piRNA Pathway". Mol. Reprod. Dev. 80 (8): 632–664. doi:10.1002/mrd.22195. PMC   4234069 . PMID   23712694.
  15. ↑ Thomson T, Lin H (2009). "The Biogenesis and Function PIWI Proteins and piRNAs: Progress and Prospect". Annu. Rev. Cell Dev. Biol. 25: 355–376. doi:10.1146/annurev.cellbio.24.110707.175327. PMC   2780330 . PMID   19575643.
  16. ↑ Cerutti L, Mian N, Bateman A (October 2000). "Domains in gene silencing and cell differentiation proteins: the novel PAZ domain and redefinition of the Piwi domain". Trends Biochem. Sci. 25 (10): 481–2. doi:10.1016/S0968-0004(00)01641-8. PMID   11050429.
  17. ↑ Ma J, Yuan Y, Meister G, Pei Y, Tuschl T, Patel D (2005). "Structural basis for 5'-end-specific recognition of guide RNA by the A. fulgidus Piwi protein". Nature. 434 (7033): 666–70. Bibcode:2005Natur.434..666M. doi:10.1038/nature03514. PMC   4694588 . PMID   15800629.
  18. ↑ Megosh HB, Cox DN, Campbell C, Lin H (2006). "The role of PIWI and the miRNA machinery in Drosophila germline determination". Curr Biol. 16 (19): 1884–94. doi: 10.1016/j.cub.2006.08.051 . PMID   16949822. S2CID   6397874.
  19. ↑ Kim VN (2006). "Small RNAs just got bigger: Piwi-interacting RNAs (piRNAs) in mammalian testes". Genes Dev. 20 (15): 1993–7. doi: 10.1101/gad.1456106 . PMID   16882976.
  20. ↑ Girard A, Sachidanandam R, Hannon GJ, Carmell MA (2006). "A germline-specific class of small RNAs binds mammalian Piwi proteins". Nature. 442 (7099): 199–202. Bibcode:2006Natur.442..199G. doi:10.1038/nature04917. PMID   16751776. S2CID   3185036.
  21. 1 2 Vagin VV, Sigova A, Li C, Seitz H, Gvozdev V, Zamore PD (2006). "A distinct small RNA pathway silences selfish genetic elements in the germline". Science. 313 (5785): 320–4. Bibcode:2006Sci...313..320V. doi:10.1126/science.1129333. PMID   16809489. S2CID   40471466.
  22. ↑ Saito K, Nishida KM, Mori T, Kawamura Y, Miyoshi K, Nagami T, Siomi H, Siomi MC (2006). "Specific association of Piwi with rasiRNAs derived from retrotransposon and heterochromatic regions in the Drosophila genome". Genes Dev. 20 (16): 2214–22. doi:10.1101/gad.1454806. PMC   1553205 . PMID   16882972.
  23. ↑ Ozata DM, Gainetdinov I, Zoch A, Phillip D, Zamore PD (2019). "PIWI-interacting RNAs: small RNAs with big functions" (PDF). Nature Reviews Genetics . 20 (2): 89–108. doi:10.1038/s41576-018-0073-3. PMID   30446728. S2CID   53565676.
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