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169  structures 1613  species 0  interactions 14038  sequences 339  architectures

Family: Piwi (PF02171)

Summary: Piwi domain

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This is the Wikipedia entry entitled "Argonaute". More...

Argonaute Edit Wikipedia article

The Argonaute protein family 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 (base pairing), which then leads to mRNA cleavage, translation inhibition, and/or the initiation of mRNA decay.[1]

The name of this protein family is derived from a mutant phenotype resulting from mutation of AGO1 in Arabidopsis thaliana, which was likened by Bohmert et al. to the appearance of the pelagic octopus Argonauta argo.[2]

Argonaute Piwi domain
An argonaute protein from Pyrococcus furiosus. PDB 1U04. PIWI domain is on the right, PAZ domain to the left.
Argonaute Paz domain
SCOP2b.34.14.1 / SCOPe / SUPFAM
Left: A full-length argonaute protein from the archaea species Pyrococcus furiosus.PDB 1U04. Right: The PIWI domain of an argonaute protein in complex with double-stranded RNA PDB 1YTU. The base-stacking interaction between the 5′ base on the guide strand and a conserved tyrosine residue (light blue) is highlighted; the stabilizing divalent cation (magnesium) is shown as a gray sphere.
Lentiviral delivery of designed shRNA's and the mechanism of RNA interference in mammalian cells.

RNA interference

RNA interference (RNAi) is a biological process in which the RNA molecules inhibit gene expression. The method of inhibition is via the destruction of specific mRNA molecules or by simply suppressing the protein translation.[3] The RNA interference has a significant role in defending cells against parasitic nucleotide sequences. In many eukaryotes, including animals, the RNA interference pathway is found, and it is initiated by the enzyme Dicer. Dicer cleaves long double-stranded RNA (dsRNA, often found in viruses and small interfering RNA) molecules into short double stranded fragments of around 20 nucleotide siRNAs. The dsRNA is then separated into two single-stranded RNAs (ssRNA) – the passenger strand and the guide strand. Subsequently, the passenger strand is degraded, while the guide strand is incorporated into the RNA-induced silencing complex (RISC). The most well-studied outcome of the RNAi is post-transcriptional gene silencing, which occurs when the guide strand pairs with a complementary sequence in a messenger RNA molecule and induces cleavage by Argonaute, that lies in the core of RNA-induced silencing complex.

Argonaute proteins are the active part of RNA-induced silencing complex, cleaving the target mRNA strand complementary to their bound siRNA.[4] Theoretically the dicer produces short double-stranded fragments so there should be also two functional single-stranded siRNA produced. But only one of the two single-stranded RNA here will be utilized to base pair with target mRNA. It is known as the guide strand, incorporated into the Argonaute protein and leads gene silencing. The other single-stranded named passenger strand is degraded during the RNA-induced silencing complex process.[5]

Once the Argonaute is associated with the small RNA, the enzymatic activity conferred by the PIWI domain cleaves only the passenger strand of the small interfering RNA. RNA strand separation and incorporation into the Argonaute protein are guided by the strength of the hydrogen bond interaction at the 5′-ends of the RNA duplex, known as the asymmetry rule. Also the degree of complementarity between the two strands of the intermediate RNA duplex defines how the miRNA are sorted into different types of Argonaute proteins.

In animals, Argonaute associated with miRNA binds to the 3′-untranslated region of mRNA and prevents the production of proteins in various ways. The recruitment of Argonaute proteins to targeted mRNA can induce mRNA degradation. The Argonaute-miRNA complex can also affect the formation of functional ribosomes at the 5′-end of the mRNA. The complex here competes with the translation initiation factors and/or abrogate ribosome assembly. Also, the Argonaute-miRNA complex can adjust protein production by recruiting cellular factors such as peptides or post translational modifying enzymes, which degrade the growing of polypeptides.[6]

In plants, once de novo double-stranded (ds) RNA duplexes are generated with the target mRNA, an unknown RNase-III-like enzyme produces new siRNAs, which are then loaded onto the Argonaute proteins containing PIWI domains, lacking the catalytic amino acid residues, which might induce another level of specific gene silencing.

Functional domains and mechanism

The Argonaute (AGO) gene family encodes for six characteristic domains: N- terminal (N), Linker-1 (L1), PAZ, Linker-2 (L2), Mid, and a C-terminal PIWI domain.[6]

The name for the PAZ domain is an acronym made from the gene names of Drosophila piwi, Arabidopsis argonaute-1, and Arabidopsis zwille (also known as poinhead, and later renamed argonaute-10), where the domain was first recognized to be conserved. The PAZ domain is an RNA binding module that recognizes single-stranded 3′ ends of siRNA, miRNA and piRNA, in a sequence independent manner.

The Drosophila PIWI protein gave its name to this characteristic motif. Structurally resembling RNaseH, the PIWI domain is essential for the target cleavage. The active site with aspartate – aspartate – glutamate triad harbors a divalent metal ion, necessary for the catalysis. Family members of AGO that lost this conserved feature during evolution will lack the cleavage activity. In human AGO, the PIWI motif also mediates protein-protein interaction at the PIWI box, where it binds to Dicer at one of the RNase III domain.[7]

At the interface of PIWI and Mid domains sits the 5′ phosphate of a siRNA, miRNA or piRNA, which is found essential in the functionality. Within Mid lies a MC motif, a homologue structure proposed to mimic the cap-binding structure motif found in eIF4E. It was later found that the MC motif is not involved in mRNA cap binding [6]

Family members

In humans, there are eight AGO family members, some of which are investigated intensively. However, even though AGO1–4 are capable of loading miRNA, endonuclease activity and thus RNAi-dependent gene silencing exclusively belongs to AGO2. Considering the sequence conservation of PAZ and PIWI domains across the family, the uniqueness of AGO2 is presumed to arise from either the N-terminus or the spacing region linking PAZ and PIWI motifs.[7]

Several AGO family members in plants also attract study. AGO1 is involved in miRNA related RNA degradation, and plays a central role in morphogenesis. In some organisms, it is strictly required for epigenetic silencing. It is regulated by miRNA itself. AGO4 does not involve in RNAi directed RNA degradation, but in DNA methylation and other epigenetic regulation, through small RNA (smRNA) pathway. AGO10 is involved in plant development. AGO7 has a function distinct from AGO 1 and 10, and is not found in gene silencing induced by transgenes. Instead, it is related to developmental timing in plants.[8]

Disease and therapeutic tools

For the diseases that are involved with selective or elevated expression of particular identified genes, such as pancreatic cancer, the high sequence specificity of RNA interference might make it suitable to be a suitable treatment, particularly appropriate for combating cancers associated with mutated endogenous gene sequences. It has been reported several tiny non-coding RNAs(microRNAs) are related with human cancers, like miR-15a and miR-16a are frequently deleted and/or down-regulated in patients. Even though the biological functions of miRNAs are not fully understood, the roles for miRNAs in the coordination of cell proliferation and cell death during development and metabolism have been uncovered. It is trusted that the miRNAs can direct negative or positive regulation at different levels, which depends on the specific miRNAs and target base pair interaction and the cofactors that recognize them.[9]

Because it has been widely known that many viruses have RNA rather than DNA as their genetic material and go through at least one stage in their life cycle when they make double-stranded RNA, RNA interference has been considered to be a potentially evolutionarily ancient mechanism for protecting organisms from viruses. The small interfering RNAs produced by Dicer cause sequence specific, post-transcriptional gene silencing by guiding an endonuclease, the RNA-induced silencing complex (RISC), to mRNA. This process has been seen in a wide range of organisms, such as Neurospora fungus (in which it is known as quelling), plants (post-transcriptional gene silencing) and mammalian cells(RNAi). If there is a complete or near complete sequence complementarity between the small RNA and the target, the Argonaute protein component of RISC mediates cleavage of the target transcript, the mechanism involves repression of translation predominantly[citation needed].

Importantly, Argonaute 4 (AGO4)-deficient influenza-infected mice have significantly higher burden and viral titers in vivo[10] which is in contrast to AGO1 or AGO3-deficient mice.[11] So, specific promotion of AGO4 function in mammalian cells may be an effective antiviral strategy.

Biotechnological applications of prokaryotic Argonaute proteins

In 2016, a group from Hebei University of Science and Technology reported genome editing using a prokaryotic Argonaute protein from Natronobacterium gregoryi. However, evidence for application of Argonaute proteins as DNA-guided nucleases for genome editing have been questioned, with the retraction of the claim from the leading journal.[12] In 2017, a group from University of Illinois reported using a prokaryotic Argonaute protein taken from Pyrococcus furiosus (PfAgo) along with guide DNA to edit DNA in vitro as artificial restriction enzymes.[13] PfAgo based artificial restriction enzymes were also used for storing data on native DNA sequences via enzymatic nicking.[14]


  1. ^ Jonas, Stefanie; Izaurralde, Elisa (2015-06-16). "Towards a molecular understanding of microRNA-mediated gene silencing". Nature Reviews Genetics. 16 (7): 421–433. doi:10.1038/nrg3965. ISSN 1471-0056.
  2. ^ Bohmert K, Camus I, Bellini C, Bouchez D, Caboche M, Benning C (January 1998). "AGO1 defines a novel locus of Arabidopsis controlling leaf development". The EMBO Journal. 17 (1): 170–180. doi:10.1093/emboj/17.1.170. PMC 1170368. PMID 9427751.
  3. ^ Guo H, Ingolia NT, Weissman JS, Bartel DP (August 2010). "Mammalian microRNAs predominantly act to decrease target mRNA levels". Nature. 466 (7308): 835–840. Bibcode:2010Natur.466..835G. doi:10.1038/nature09267. PMC 2990499. PMID 20703300.
  4. ^ Kupferschmidt K (August 2013). "A lethal dose of RNA". Science. 341 (6147): 732–733. Bibcode:2013Sci...341..732K. doi:10.1126/science.341.6147.732. PMID 23950525.
  5. ^ Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R (November 2005). "Human RISC couples microRNA biogenesis and posttranscriptional gene silencing". Cell. 123 (4): 631–640. doi:10.1016/j.cell.2005.10.022. PMID 16271387.
  6. ^ a b c Hutvagner G, Simard MJ (January 2008). "Argonaute proteins: key players in RNA silencing". Nature Reviews. Molecular Cell Biology. 9 (1): 22–32. doi:10.1038/nrm2321. hdl:10453/15429. PMID 18073770. S2CID 8822503.
  7. ^ a b Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T (July 2004). "Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs". Molecular Cell. 15 (2): 185–197. doi:10.1016/j.molcel.2004.07.007. PMID 15260970.
  8. ^ Meins F, Si-Ammour A, Blevins T (2005). "RNA silencing systems and their relevance to plant development". Annual Review of Cell and Developmental Biology. 21 (1): 297–318. doi:10.1146/annurev.cellbio.21.122303.114706. PMID 16212497.
  9. ^ Hannon GJ (July 2002). "RNA interference". Nature. 418 (6894): 244–251. Bibcode:2002Natur.418..244H. doi:10.1038/418244a. PMID 12110901.
  10. ^ Adiliaghdam, F., Basavappa, M., Saunders, T. L., Harjanto, D., Prior, J. T., Cronkite, D. A., ... & Jeffrey, K. L. (2020). A Requirement for Argonaute 4 in Mammalian Antiviral Defense. Cell reports, 30(6), 1690-1701. doi:10.1016/j.celrep.2020.01.021 PMC 7039342 PMID 32049003
  11. ^ Van Stry, M., Oguin, T. H., Cheloufi, S., Vogel, P., Watanabe, M., Pillai, M. R., ... & Bix, M. (2012). Enhanced susceptibility of Ago1/3 double-null mice to influenza A virus infection. Journal of virology, 86(8), 4151-4157. doi:10.1128/JVI.05303-11 PMC 3318639 PMID 22318144
  12. ^ Cyranoski D (2017). "Authors retract controversial NgAgo gene-editing study". Nature. doi:10.1038/nature.2017.22412.
  13. ^ Enghiad B, Zhao H (May 2017). "Programmable DNA-Guided Artificial Restriction Enzymes". ACS Synthetic Biology. 6 (5): 752–757. doi:10.1021/acssynbio.6b00324. PMID 28165224. S2CID 3833124.
  14. ^ Tabatabaei, S. Kasra; Wang, Boya; Athreya, Nagendra Bala Murali; Enghiad, Behnam; Hernandez, Alvaro Gonzalo; Fields, Christopher J.; Leburton, Jean-Pierre; Soloveichik, David; Zhao, Huimin; Milenkovic, Olgica (8 April 2020). "DNA punch cards for storing data on native DNA sequences via enzymatic nicking". Nature Communications. 11 (1): 1742. Bibcode:2020NatCo..11.1742T. doi:10.1038/s41467-020-15588-z. PMC 7142088. PMID 32269230.

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This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Piwi". More...

Piwi Edit Wikipedia article

Piwi domain
PDB 1z26 EBI.jpg
Structure of the Pyrococcus furiosus Argonaute protein.[1]
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.[2]
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).[3]

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 in Drosophila.[5] Piwi proteins are highly conserved RNA-binding proteins and are present in both plants and animals.[6] 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 slicer activity conferred by the presence of the Piwi domain.[7] 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.

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.[8][9] 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.[8]

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.[10]

One of the major human homologues, whose upregulation is implicated in the formation of tumours such as seminomas, is called hiwi (for human piwi).[11]

Homologous proteins in mice have been called miwi (for mouse piwi).[12]

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.[13] 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,[14] 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[15] 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.[16]

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.[17]

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.[18] 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[19] 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.[20] piRNAs have thus been classified as repeat-associated small interfering RNAs (rasiRNAs).[21]

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.[20][22]


  1. ^ a b Rivas FV, Tolia NH, Song JJ, et al. (April 2005). "Purified Argonaute2 and an siRNA form recombinant human RISC". Nat. Struct. Mol. Biol. 12 (4): 340–9. doi:10.1038/nsmb918. PMID 15800637. S2CID 2021813.
  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 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. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ a b 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.
  19. ^ 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.
  20. ^ a b 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.
  21. ^ 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.
  22. ^ 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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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Piwi domain Provide feedback

This domain is found in the protein Piwi and its relatives. The function of this domain is the dsRNA guided hydrolysis of ssRNA. Determination of the crystal structure of Argonaute reveals that PIWI is an RNase H domain, and identifies Argonaute as Slicer, the enzyme that cleaves mRNA in the RNAi RISC complex [2]. In addition, Mg+2 dependence and production of 3'-OH and 5' phosphate products are shared characteristics of RNaseH and RISC. The PIWI domain core has a tertiary structure belonging to the RNase H family of enzymes. RNase H fold proteins all have a five-stranded mixed beta-sheet surrounded by helices. By analogy to RNase H enzymes which cleave single-stranded RNA guided by the DNA strand in an RNA/DNA hybrid, the PIWI domain can be inferred to cleave single-stranded RNA, for example mRNA, guided by double stranded siRNA.

Literature references

  1. Cerutti L, Mian N, Bateman A; , Trends Biochem Sci 2000;25:481-482.: Domains in gene silencing and cell differentiation proteins: the novel PAZ domain and redefinition of the Piwi domain. PUBMED:11050429 EPMC:11050429

  2. Song JJ, Smith SK, Hannon GJ, Joshua-Tor L; , Science 2004;305:1434-1437.: Crystal structure of Argonaute and its implications for RISC slicer activity. PUBMED:15284453 EPMC:15284453

Internal database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR003165

The piwi domain [ PUBMED:11050429 ] 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, as has been determined in the argonaute family of related proteins [ PUBMED:15284453 ].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

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HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Bateman A
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Bateman A , Hammonds G
Number in seed: 15
Number in full: 14038
Average length of the domain: 265.10 aa
Average identity of full alignment: 37 %
Average coverage of the sequence by the domain: 34.14 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 28.9 28.9
Trusted cut-off 28.9 28.9
Noise cut-off 28.8 28.8
Model length: 302
Family (HMM) version: 20
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Tree controls


The tree shows the occurrence of this domain across different species. More...


Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.


For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Piwi domain has been found. There are 169 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0P0V142 View 3D Structure Click here
A0A0P0VVI1 View 3D Structure Click here
A0A0P0W4J5 View 3D Structure Click here
A0A0R0F065 View 3D Structure Click here
A0A0R0G540 View 3D Structure Click here
A0A0R0I2I5 View 3D Structure Click here
A0A0R0I9G1 View 3D Structure Click here
A0A0R0JXM9 View 3D Structure Click here
A0A0T7CIX3 View 3D Structure Click here
A0A0U1RML5 View 3D Structure Click here
A0A1D6DZF2 View 3D Structure Click here
A0A1D6E2V1 View 3D Structure Click here
A0A1D6EIX2 View 3D Structure Click here
A0A1D6EVH9 View 3D Structure Click here
A0A1D6F8V7 View 3D Structure Click here
A0A1D6FB88 View 3D Structure Click here
A0A1D6FHZ8 View 3D Structure Click here
A0A1D6FPU2 View 3D Structure Click here
A0A1D6FWE3 View 3D Structure Click here
A0A1D6GFG2 View 3D Structure Click here
A0A1D6GKG3 View 3D Structure Click here
A0A1D6GUC8 View 3D Structure Click here
A0A1D6GWY2 View 3D Structure Click here
A0A1D6H369 View 3D Structure Click here
A0A1D6H4L3 View 3D Structure Click here
A0A1D6H6L5 View 3D Structure Click here
A0A1D6H6U3 View 3D Structure Click here
A0A1D6HA23 View 3D Structure Click here
A0A1D6HNX1 View 3D Structure Click here
A0A1D6I0T3 View 3D Structure Click here
A0A1D6IAA8 View 3D Structure Click here
A0A1D6IHT4 View 3D Structure Click here
A0A1D6ILX0 View 3D Structure Click here
A0A1D6J4L3 View 3D Structure Click here
A0A1D6J6J0 View 3D Structure Click here
A0A1D6J778 View 3D Structure Click here
A0A1D6J8M6 View 3D Structure Click here
A0A1D6JCD6 View 3D Structure Click here
A0A1D6JD18 View 3D Structure Click here
A0A1D6JEA5 View 3D Structure Click here