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0  structures 27  species 0  interactions 42  sequences 1  architecture

Family: PH_15 (PF17339)

Summary: PH domain

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Domain of unknown function". More...

Domain of unknown function Edit Wikipedia article

A domain of unknown function (DUF) is a protein domain that has no characterised function. These families have been collected together in the Pfam database using the prefix DUF followed by a number, with examples being DUF2992 and DUF1220. As of 2019, there are almost 4,000 DUF families within the Pfam database representing over 22% of known families. Some DUFs are not named using the nomenclature due to popular usage but are nevertheless DUFs.[1]

The DUF designation is tentative, and such families tend to be renamed to a more specific name (or merged to an existing domain) after a function is identified.[2][3]


The DUF naming scheme was introduced by Chris Ponting, through the addition of DUF1 and DUF2 to the SMART database.[4] These two domains were found to be widely distributed in bacterial signaling proteins. Subsequently, the functions of these domains were identified and they have since been renamed as the GGDEF domain and EAL domain respectively.[2]


Structural genomics programmes have attempted to understand the function of DUFs through structure determination. The structures of over 250 DUF families have been solved. This (2009) work showed that about two thirds of DUF families had a structure similar to a previously solved one and therefore likely to be divergent members of existing protein superfamilies, whereas about one third possessed a novel protein fold.[5]

Some DUF families share remote sequence homology with domains that has characterized function. Computational work can be used to link these relationships. An 2015 work was able to assign 20% of the DUFs to characterized structual superfamilies.[6] Pfam also continuously perform the (manually-verified) assignment in "clan" superfamily entries.[1]

Frequency and conservation

Protein domains and DUFs in different domains of life. Left: Annotated domains. Right: domains of unknown function. Not all overlaps shown.[7]

More than 20% of all protein domains were annotated as DUFs in 2013. About 2,700 DUFs are found in bacteria compared with just over 1,500 in eukaryotes. Over 800 DUFs are shared between bacteria and eukaryotes, and about 300 of these are also present in archaea. A total of 2,786 bacterial Pfam domains even occur in animals, including 320 DUFs.[7]

Role in biology

Many DUFs are highly conserved, indicating an important role in biology. However, many such DUFs are not essential, hence their biological role often remains unknown. For instance, DUF143 is present in most bacteria and eukaryotic genomes.[8] However, when it was deleted in Escherichia coli no obvious phenotype was detected. Later it was shown that the proteins that contain DUF143, are ribosomal silencing factors that block the assembly of the two ribosomal subunits.[8] While this function is not essential, it helps the cells to adapt to low nutrient conditions by shutting down protein biosynthesis. As a result, these proteins and the DUF only become relevant when the cells starve.[8] It is thus believed that many DUFs (or proteins of unknown function, PUFs) are only required under certain conditions.

Essential DUFs

Goodacre et al. identified 238 DUFs in 355 essential proteins (in 16 model bacterial species), most of which represent single-domain proteins, clearly establishing the biological essentiality of DUFs. These DUFs are called "essential DUFs" or eDUFs.[7]

External links


  1. ^ a b El-Gebali S, Mistry J, Bateman A, Eddy SR, Luciani A, Potter SC, Qureshi M, Richardson LJ, Salazar GA, Smart A, Sonnhammer EL, Hirsh L, Paladin L, Piovesan D, Tosatto SC, Finn RD (January 2019). "The Pfam protein families database in 2019". Nucleic Acids Research. 47 (D1): D427–D432. doi:10.1093/nar/gky995. PMC 6324024. PMID 30357350.
  2. ^ a b Bateman A, Coggill P, Finn RD (October 2010). "DUFs: families in search of function". Acta Crystallographica. Section F, Structural Biology and Crystallization Communications. 66 (Pt 10): 1148–52. doi:10.1107/S1744309110001685. PMC 2954198. PMID 20944204.
  3. ^ Punta M, Coggill PC, Eberhardt RY, Mistry J, Tate J, Boursnell C, Pang N, Forslund K, Ceric G, Clements J, Heger A, Holm L, Sonnhammer EL, Eddy SR, Bateman A, Finn RD (January 2012). "The Pfam protein families database". Nucleic Acids Research. 40 (Database issue): D290–301. doi:10.1093/nar/gkr1065. PMC 3245129. PMID 22127870.
  4. ^ Schultz J, Milpetz F, Bork P, Ponting CP (May 1998). "SMART, a simple modular architecture research tool: identification of signaling domains". Proceedings of the National Academy of Sciences of the United States of America. 95 (11): 5857–64. Bibcode:1998PNAS...95.5857S. doi:10.1073/pnas.95.11.5857. PMC 34487. PMID 9600884.
  5. ^ Jaroszewski L, Li Z, Krishna SS, Bakolitsa C, Wooley J, Deacon AM, Wilson IA, Godzik A (September 2009). "Exploration of uncharted regions of the protein universe". PLoS Biology. 7 (9): e1000205. doi:10.1371/journal.pbio.1000205. PMC 2744874. PMID 19787035.
  6. ^ Mudgal R, Sandhya S, Chandra N, Srinivasan N (July 2015). "De-DUFing the DUFs: Deciphering distant evolutionary relationships of Domains of Unknown Function using sensitive homology detection methods". Biology Direct. 10 (1): 38. doi:10.1186/s13062-015-0069-2. PMC 4520260. PMID 26228684.
  7. ^ a b c Goodacre NF, Gerloff DL, Uetz P (December 2013). "Protein domains of unknown function are essential in bacteria". mBio. 5 (1): e00744–13. doi:10.1128/mBio.00744-13. PMC 3884060. PMID 24381303.
  8. ^ a b c Häuser R, Pech M, Kijek J, Yamamoto H, Titz B, Naeve F, Tovchigrechko A, Yamamoto K, Szaflarski W, Takeuchi N, Stellberger T, Diefenbacher ME, Nierhaus KH, Uetz P (2012). Hughes D (ed.). "RsfA (YbeB) proteins are conserved ribosomal silencing factors". PLoS Genetics. 8 (7): e1002815. doi:10.1371/journal.pgen.1002815. PMC 3400551. PMID 22829778.

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 "Pleckstrin homology domain". More...

Pleckstrin homology domain Edit Wikipedia article

1bwn opm.png
PH domain of tyrosine-protein kinase BTK
Pfam clanCL0266
OPM superfamily49
OPM protein1pls

Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton.[1][2][3][4][5][6][7]

This domain can bind phosphatidylinositol lipids within biological membranes (such as phosphatidylinositol (3,4,5)-trisphosphate and phosphatidylinositol (4,5)-bisphosphate),[8] and proteins such as the βγ-subunits of heterotrimeric G proteins,[9] and protein kinase C.[10] Through these interactions, PH domains play a role in recruiting proteins to different membranes, thus targeting them to appropriate cellular compartments or enabling them to interact with other components of the signal transduction pathways.

Lipid binding specificity

Individual PH domains possess specificities for phosphoinositides phosphorylated at different sites within the inositol ring, e.g., some bind phosphatidylinositol (4,5)-bisphosphate but not phosphatidylinositol (3,4,5)-trisphosphate or phosphatidylinositol (3,4)-bisphosphate, while others may possess the requisite affinity. This is important because it makes the recruitment of different PH domain containing proteins sensitive to the activities of enzymes that either phosphorylate or dephosphorylate these sites on the inositol ring, such as phosphoinositide 3-kinase or PTEN, respectively. Thus, such enzymes exert a part of their effect on cell function by modulating the localization of downstream signaling proteins that possess PH domains that are capable of binding their phospholipid products.


The 3D structure of several PH domains has been determined.[11] All known cases have a common structure consisting of two perpendicular anti-parallel beta sheets, followed by a C-terminal amphipathic helix. The loops connecting the beta-strands differ greatly in length, making the PH domain relatively difficult to detect while providing the source of the domain's specificity. The only conserved residue among PH domains is a single tryptophan located within the alpha helix that serves to nucleate the core of the domain.

Proteins containing PH domain

PH domains can be found in many different proteins, such as OSBP or ARF. Recruitment to the Golgi in this case is dependent on both PtdIns and ARF. A large number of PH domains have poor affinity for phosphoinositides and are hypothesized to function as protein binding domains. A Genome-wide look in Saccharomyces cerevisiae showed that most of the 33 yeast PH domains are indeed promiscuous in binding to phosphoinositides, while only one (Num1-PH) behaved highly specific .[12] Proteins reported to contain PH domains belong to the following families:

  • Pleckstrin, the protein where this domain was first detected, is the major substrate of protein kinase C in platelets. Pleckstrin contains two PH domains. ARAP proteins contain five PH domains.
  • Ser/Thr protein kinases such as the Akt/Rac family, the beta-adrenergic receptor kinases, the mu isoform of PKC and the trypanosomal NrkA family.
  • Tyrosine protein kinases belonging to the Btk/Itk/Tec subfamily.
  • Insulin receptor substrate 1 (IRS-1).
  • Regulators of small G-proteins: 64 RhoGEFs of the Dbl-like family. [13], and several GTPase activating proteins like ABR, BCR or ARAP proteins.
  • Cytoskeletal proteins such as dynamin (see InterProIPR001401), Caenorhabditis elegans kinesin-like protein unc-104 (see InterProIPR001752), spectrin beta-chain, syntrophin (2 PH domains), and S. cerevisiae nuclear migration protein NUM1.
  • Oxysterol-binding proteins OSBP, S. cerevisiae OSH1 and YHR073w.
  • Ceramide kinase, a lipid kinase that phosphorylates ceramides to ceramide-1-phosphate.
  • G protein receptor kinases 2 (GRK2) subfamily 2: GRK2 and GRK3 [14]

Sugiura M, Kono K, Liu H, Shimizugawa T, Minekura H, Spiegel S, Kohama T (June 2002). "Ceramide kinase, a novel lipid kinase. Molecular cloning and functional characterization". The Journal of Biological Chemistry. 277 (26): 23294–300. doi:10.1074/jbc.M201535200. PMID 11956206.</ref>



Human genes encoding proteins containing this domain include:

See also


  1. ^ Mayer BJ, Ren R, Clark KL, Baltimore D (May 1993). "A putative modular domain present in diverse signaling proteins". Cell. 73 (4): 629–30. doi:10.1016/0092-8674(93)90244-K. PMID 8500161.
  2. ^ Haslam RJ, Koide HB, Hemmings BA (May 1993). "Pleckstrin domain homology". Nature. 363 (6427): 309–10. doi:10.1038/363309b0. PMID 8497315.
  3. ^ Musacchio A, Gibson T, Rice P, Thompson J, Saraste M (September 1993). "The PH domain: a common piece in the structural patchwork of signalling proteins". Trends in Biochemical Sciences. 18 (9): 343–8. doi:10.1016/0968-0004(93)90071-T. PMID 8236453.
  4. ^ Gibson TJ, Hyvönen M, Musacchio A, Saraste M, Birney E (September 1994). "PH domain: the first anniversary". Trends in Biochemical Sciences. 19 (9): 349–53. doi:10.1016/0968-0004(94)90108-2. PMID 7985225.
  5. ^ Pawson T (February 1995). "Protein modules and signalling networks". Nature. 373 (6515): 573–80. doi:10.1038/373573a0. PMID 7531822.
  6. ^ Ingley E, Hemmings BA (December 1994). "Pleckstrin homology (PH) domains in signal transduction". Journal of Cellular Biochemistry. 56 (4): 436–43. doi:10.1002/jcb.240560403. PMID 7890802.
  7. ^ Saraste M, Hyvönen M (June 1995). "Pleckstrin homology domains: a fact file". Current Opinion in Structural Biology. 5 (3): 403–8. doi:10.1016/0959-440X(95)80104-9. PMID 7583640.
  8. ^ Wang DS, Shaw G (December 1995). "The association of the C-terminal region of beta I sigma II spectrin to brain membranes is mediated by a PH domain, does not require membrane proteins, and coincides with a inositol-1,4,5 triphosphate binding site". Biochemical and Biophysical Research Communications. 217 (2): 608–15. doi:10.1006/bbrc.1995.2818. PMID 7503742.
  9. ^ Wang DS, Shaw R, Winkelmann JC, Shaw G (August 1994). "Binding of PH domains of beta-adrenergic receptor kinase and beta-spectrin to WD40/beta-transducin repeat containing regions of the beta-subunit of trimeric G-proteins". Biochemical and Biophysical Research Communications. 203 (1): 29–35. doi:10.1006/bbrc.1994.2144. PMID 8074669.
  10. ^ Yao L, Kawakami Y, Kawakami T (September 1994). "The pleckstrin homology domain of Bruton tyrosine kinase interacts with protein kinase C". Proceedings of the National Academy of Sciences of the United States of America. 91 (19): 9175–9. doi:10.1073/pnas.91.19.9175. PMC 44770. PMID 7522330.
  11. ^ Riddihough G (November 1994). "More meanders and sandwiches". Nature Structural Biology. 1 (11): 755–7. doi:10.1038/nsb1194-755. PMID 7634082.
  12. ^ Yu JW, Mendrola JM, Audhya A, Singh S, Keleti D, DeWald DB, Murray D, Emr SD, Lemmon MA (March 2004). "Genome-wide analysis of membrane targeting by S. cerevisiae pleckstrin homology domains". Molecular Cell. 13 (5): 677–88. doi:10.1016/S1097-2765(04)00083-8. PMID 15023338.
  13. ^ Fort P, Blangy A (June 2017). "The Evolutionary Landscape of Dbl-Like RhoGEF Families: Adapting Eukaryotic Cells to Environmental Signals". Genome Biol Evol. 9 (6): 1471–1486. doi:10.1093/gbe/evx100. PMC 5499878. PMID 28541439.
  14. ^ Komolov KE, Benovic JL (January 2018). "G protein-coupled receptor kinases: Past, present and future". Cellular Signalling. 41: 17–24. doi:10.1016/j.cellsig.2017.07.004. PMC 5722692. PMID 28711719.

External links

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

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.

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This entry contains a PH domain.

Internal database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR040443

This entry represents the PH domain found in PHLA2/3. Mouse PHLA2, also known as Tssc3 or Ipl, plays a role in regulating placenta growth [PUBMED:12032310]. Human PHLDA3 is a p53-regulated repressor that competes with the PH domain of Akt for binding of membrane lipids, thereby regulates the Akt pathway [PUBMED:19203586].

Domain organisation

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We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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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: PRODOM:PD041151
Previous IDs: DUF5369;
Type: Domain
Sequence Ontology: SO:0000417
Author: El-Gebali S , Bateman A
Number in seed: 8
Number in full: 42
Average length of the domain: 94.80 aa
Average identity of full alignment: 33 %
Average coverage of the sequence by the domain: 34.05 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 22.8 22.8
Trusted cut-off 22.9 22.8
Noise cut-off 22.7 22.5
Model length: 107
Family (HMM) version: 3
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Species distribution

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


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