Pleckstrin homology domain

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.

Structure

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 apparatus 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.
• Serine/threonine-specific protein kinases such as the Akt/Rac family, protein kinase D1, and the trypanosomal NrkA family.
• Non-receptor tyrosine 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 ), Caenorhabditis elegans kinesin-like protein unc-104 (see ), 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.{{cite journal
• G protein receptor kinases (GRK) of GRK2 subfamily (beta-adrenergic receptor kinases): GRK2 and GRK3.

Clinical significance

Heterozygous loss of function mutations in the PHIP gene result in Chung-Jansen syndrome -also called PHIP-related disorder. This disorder is mainly characterized by developmental delay (DD), learning difficulties/intellectual disability (ID), behavioral abnormalities, facial dysmorphism and obesity (CHUJANS, OMIM #617991).

Subfamilies

• Spectrin/pleckstrin-like

Examples

Human genes encoding proteins containing this domain include:

• ABR, ADAP2, 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, CENTB1, CENTB2, CENTB5, CENTD1, CENTD2, CENTD3, CENTG1, CENTG2, CENTG3, CERK, 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,
• EXOC8,
• 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

References

References

1. (May 1993). "A putative modular domain present in diverse signaling proteins". Cell.
2. (May 1993). "Pleckstrin domain homology". Nature.
3. (September 1993). "The PH domain: a common piece in the structural patchwork of signalling proteins". Trends in Biochemical Sciences.
4. (September 1994). "PH domain: the first anniversary". Trends in Biochemical Sciences.
5. (February 1995). "Protein modules and signalling networks". Nature.
6. (December 1994). "Pleckstrin homology (PH) domains in signal transduction". Journal of Cellular Biochemistry.
7. (June 1995). "Pleckstrin homology domains: a fact file". Current Opinion in Structural Biology.
8. (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.
9. (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.
10. (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.
11. (November 1994). "More meanders and sandwiches". Nature Structural Biology.
12. (March 2004). "Genome-wide analysis of membrane targeting by S. cerevisiae pleckstrin homology domains". Molecular Cell.
13. (June 2017). "The Evolutionary Landscape of Dbl-Like RhoGEF Families: Adapting Eukaryotic Cells to Environmental Signals". Genome Biol Evol.
14. (January 2018). "G protein-coupled receptor kinases: Past, present and future". Cellular Signalling.
15. (January 2018). "A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency". European Journal of Human Genetics.
16. (2023-01-16). "PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals". Frontiers in Cell and Developmental Biology.