Pleckstrin homology domain
PH domain of tyrosine-protein kinase BTK
|SCOPe||1dyn / SUPFAM|
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.
This domain can bind phosphatidylinositol lipids within biological membranes (such as phosphatidylinositol (3,4,5)-trisphosphate and phosphatidylinositol (4,5)-bisphosphate), and proteins such as the βγ-subunits of heterotrimeric G proteins, and protein kinase C. 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. 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 . 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. , and several GTPase activating proteins like ABR, BCR or ARAP proteins.
- Cytoskeletal proteins such as dynamin (see InterPro: IPR001401), Caenorhabditis elegans kinesin-like protein unc-104 (see InterPro: IPR001752), 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 
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:
- ABR, ADRBK1, ADRBK2, AFAP, AFAP1, AFAP1L1, AFAP1L2, AKAP13, AKT1, AKT2, AKT3, ANLN, APBB1IP, APPL1, APPL2, ARHGAP10, ARHGAP12, ARHGAP15, ARHGAP21, ARHGAP22, ARHGAP23, ARHGAP24, ARHGAP25, ARHGAP26, ARHGAP27, ARHGAP9, ARHGEF16, ARHGEF18, ARHGEF19, ARHGEF2, ARHGEF3, ARHGEF4, ARHGEF5, ARHGEF6, ARHGEF7, ARHGEF9, ASEF2,
- BMX, BTK,
- C20orf42, C9orf100, CADPS, CADPS2, CDC42BPA, CDC42BPB, CDC42BPG, CENTA1, CENTA2, CENTB1, CENTB2, CENTB5, CENTD1, CENTD2, CENTD3, CENTG1, CENTG2, CENTG3, CIT, CNKSR1, CNKSR2, COL4A3BP, CTGLF1, CTGLF2, CTGLF3, * CTGLF4, CTGLF5, CTGLF6,
- DAB2IP, DAPP1, DDEF1, DDEF2, DDEFL1, DEF6, DEPDC2, DGKD, DGKH, DGKK, DNM1, DNM2, DNM3, DOCK10, DOCK11, DOCK9, DOK1, DOK2, DOK3, DOK4, DOK5, DOK6, DTGCU2,
- FAM109A, FAM109B, FARP1, FARP2, FGD1, FGD2, FGD3, FGD4, FGD5, FGD6,
- GAB1, GAB2, GAB3, GAB4, GRB10, GRB14, GRB7,
- IRS1, IRS2, IRS4, ITK, ITSN1, ITSN2,
- KALRN, KIF1A, KIF1B, KIF1Bbeta,
- MCF2, MCF2L, MCF2L2, MRIP, MYO10,
- NET1, NGEF,
- OBPH1, OBSCN, OPHN1, OSBP, OSBP2, OSBPL10, OSBPL11, OSBPL3, OSBPL5, OSBPL6, OSBPL7, OSBPL8, OSBPL9,
- PHLDA2, PHLDA3, PHLDB1, PHLDB2, PHLPP, PIP3-E, PLCD1, PLCD4, PLCG1, PLCG2, PLCH1, PLCH2, PLCL1, PLCL2, PLD1, PLD2, PLEK, PLEK2, PLEKHA1, PLEKHA2, PLEKHA3, PLEKHA4, PLEKHA5, PLEKHA6, PLEKHA7, PLEKHA8, PLEKHB1, PLEKHB2, PLEKHC1, PLEKHF1, PLEKHF2, PLEKHG1, PLEKHG2, PLEKHG3, PLEKHG4, PLEKHG5, PLEKHG6, PLEKHH1, PLEKHH2, PLEKHH3, PLEKHJ1, PLEKHK1, PLEKHM1, PLEKHM2, PLEKHO1, PLEKHQ1, PREX1, PRKCN, PRKD1, PRKD2, PRKD3, PSCD1, PSCD2, PSCD3, PSCD4, PSD, PSD2, PSD3, PSD4, RALGPS1, RALGPS2, RAPH1,
- RASA1, RASA2, RASA3, RASA4, RASAL1, RASGRF1, RGNEF, ROCK1, ROCK2, RTKN,
- SBF1, SBF2, SCAP2, SGEF, SH2B, SH2B1, SH2B2, SH2B3, SH3BP2, SKAP1, SKAP2, SNTA1, SNTB1, SNTB2, SOS1, SOS2, SPATA13, SPNB4, SPTBN1, SPTBN2, SPTBN4, SPTBN5, STAP1, SWAP70, SYNGAP1,
- TBC1D2, TEC, TIAM1, TRIO, TRIOBP, TYL,
- URP1, URP2,
- VAV1, VAV2, VAV3, VEPH1
- The unrelated FYVE domain binds Phosphatidylinositol 3-phosphate and has been found in over 60 proteins.
- The GRAM domain is a structurally related protein domain.
- 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.
- Haslam RJ, Koide HB, Hemmings BA (May 1993). "Pleckstrin domain homology". Nature. 363 (6427): 309–10. doi:10.1038/363309b0. PMID 8497315.
- 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.
- 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.
- Pawson T (February 1995). "Protein modules and signalling networks". Nature. 373 (6515): 573–80. doi:10.1038/373573a0. PMID 7531822.
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- 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.
- 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.
- 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.
- 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.
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- 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.
- 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.
- 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.
- Nash Lab Protein Interaction Domains - PH domain description
- UMich Orientation of Proteins in Membranes families/superfamily-51 - Calculated orientations of PH domains in membranes