Pleckstrin homology domain explained

Symbol:	PH
Width:	250
Pfam:	PF00169
Pfam Clan:	CL0266
Interpro:	IPR001849
Smart:	PH
Prosite:	PDOC50003
Scop:	1dyn
Cdd:	cd00821
Opm Family:	49
Opm Protein:	1pls

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.

Structure

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 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 .^[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.
• 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.,^[13] 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.^[14]
• G protein receptor kinases (GRK) of GRK2 subfamily (beta-adrenergic receptor kinases): GRK2 and GRK3.^[15]

Subfamilies

• Spectrin/pleckstrin-like

Examples

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, 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

See also

• Pleckstrin
• 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.

External links

• Nash Lab Protein Interaction Domains - PH domain description
• - Calculated orientations of PH domains in membranes

Notes and References

1. Mayer BJ, Ren R, Clark KL, Baltimore D . A putative modular domain present in diverse signaling proteins . Cell . 73 . 4 . 629–30 . May 1993 . 8500161 . 10.1016/0092-8674(93)90244-K . 44282241 .
2. Haslam RJ, Koide HB, Hemmings BA . Pleckstrin domain homology . Nature . 363 . 6427 . 309–10 . May 1993 . 8497315 . 10.1038/363309b0 . 1993Natur.363..309H . 4334376 .
3. Musacchio A, Gibson T, Rice P, Thompson J, Saraste M . The PH domain: a common piece in the structural patchwork of signalling proteins . Trends in Biochemical Sciences . 18 . 9 . 343–8 . September 1993 . 8236453 . 10.1016/0968-0004(93)90071-T .
4. Gibson TJ, Hyvönen M, Musacchio A, Saraste M, Birney E . PH domain: the first anniversary . Trends in Biochemical Sciences . 19 . 9 . 349–53 . September 1994 . 7985225 . 10.1016/0968-0004(94)90108-2 . Ewan Birney . free .
5. Pawson T . Protein modules and signalling networks . Nature . 373 . 6515 . 573–80 . February 1995 . 7531822 . 10.1038/373573a0 . 1995Natur.373..573P . 4324726 .
6. Ingley E, Hemmings BA . Pleckstrin homology (PH) domains in signal transduction . Journal of Cellular Biochemistry . 56 . 4 . 436–43 . December 1994 . 7890802 . 10.1002/jcb.240560403 . 23154429 .
7. Saraste M, Hyvönen M . Pleckstrin homology domains: a fact file . Current Opinion in Structural Biology . 5 . 3 . 403–8 . June 1995 . 7583640 . 10.1016/0959-440X(95)80104-9 .
8. Wang DS, Shaw G . 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 . December 1995 . 7503742 . 10.1006/bbrc.1995.2818 .
9. Wang DS, Shaw R, Winkelmann JC, Shaw G . 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 . August 1994 . 8074669 . 10.1006/bbrc.1994.2144 .
10. Yao L, Kawakami Y, Kawakami T . 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 . September 1994 . 7522330 . 10.1073/pnas.91.19.9175 . 44770 . 1994PNAS...91.9175Y . free .
11. Riddihough G . More meanders and sandwiches . Nature Structural Biology . 1 . 11 . 755–7 . November 1994 . 7634082 . 10.1038/nsb1194-755 . 5410578 .
12. Yu JW, Mendrola JM, Audhya A, Singh S, Keleti D, DeWald DB, Murray D, Emr SD, Lemmon MA . Genome-wide analysis of membrane targeting by S. cerevisiae pleckstrin homology domains . Molecular Cell . 13 . 5 . 677–88 . March 2004 . 15023338 . 10.1016/S1097-2765(04)00083-8 . Mark A. Lemmon . free .
13. Fort P, Blangy A . The Evolutionary Landscape of Dbl-Like RhoGEF Families: Adapting Eukaryotic Cells to Environmental Signals . Genome Biol Evol . 9 . 6 . 1471–1486 . June 2017 . 28541439 . 10.1093/gbe/evx100 . 5499878.
14. Sugiura M, Kono K, Liu H, Shimizugawa T, Minekura H, Spiegel S, Kohama T . Ceramide kinase, a novel lipid kinase. Molecular cloning and functional characterization . The Journal of Biological Chemistry . 277 . 26 . 23294–300 . June 2002 . 11956206 . 10.1074/jbc.M201535200 . free .
15. Komolov KE, Benovic JL . G protein-coupled receptor kinases: Past, present and future . Cellular Signalling . 41 . 17–24 . January 2018 . 28711719 . 5722692 . 10.1016/j.cellsig.2017.07.004 .