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0  structures 413  species 0  interactions 432  sequences 6  architectures

Family: PH_6 (PF15406)

Summary: Pleckstrin homology domain

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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

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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.

Pleckstrin homology domain Provide feedback

This Pleckstrin homology domain is found in some fungal species.

Literature references

  1. Gibson TJ, Hyvonen M, Musacchio A, Saraste M, Birney E; , Trends Biochem Sci 1994;19:349-353.: PH domain: the first anniversary. PUBMED:7985225 EPMC:7985225

Internal database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR039483

This entry represents the PH domain found in Meu6 (meiotic expression up-regulated protein 6). The function of Meu6 is not clear.

Domain organisation

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Curation and family details

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Curation View help on the curation process

Seed source: Jackhmmer:O94356
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Wood V , Coggill P
Number in seed: 11
Number in full: 432
Average length of the domain: 108.10 aa
Average identity of full alignment: 47 %
Average coverage of the sequence by the domain: 18.72 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 30.0 30.0
Trusted cut-off 30.0 30.0
Noise cut-off 29.9 29.9
Model length: 112
Family (HMM) version: 8
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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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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
O94356 View 3D Structure Click here

trRosetta Structure

The structural model below was generated by the Baker group with the trRosetta software using the Pfam UniProt multiple sequence alignment.

The InterPro website shows the contact map for the Pfam SEED alignment. Hovering or clicking on a contact position will highlight its connection to other residues in the alignment, as well as on the 3D structure.

Improved protein structure prediction using predicted inter-residue orientations. Jianyi Yang, Ivan Anishchenko, Hahnbeom Park, Zhenling Peng, Sergey Ovchinnikov, David Baker Proceedings of the National Academy of Sciences Jan 2020, 117 (3) 1496-1503; DOI: 10.1073/pnas.1914677117;