Pleckstrin homology domain

Pfam_box
Symbol = PH
Name =

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width =250
caption =PH domain of tyrosine-protein kinase BTK
Pfam= PF00169
InterPro= IPR001849
SMART= PH
PROSITE=PDOC50003
SCOP = 1dyn
TCDB =
OPM family= 51
OPM protein= 1pls
PDB=PDB3|1dynB:520-625 PDB3|2dynA:520-625 PDB3|1pls :5-101PDB3|1eazA:192-289 PDB3|1xx0A:245-347 PDB3|1x05A:245-347PDB3|1x1gA:248-352 PDB3|1u27A:260-376 PDB3|1u29A:260-376PDB3|1u2bA:265-380 PDB3|1fhxB:265-380 PDB3|1fgzA:265-380PDB3|1fgyA:265-380 PDB3|1faoA:165-259 PDB3|1fb8A:165-259PDB3|1v89A:40-144 PDB3|1upqA:55-153 PDB3|1uprA:55-153PDB3|1qqgB:13-115 PDB3|1wg7A:175-281 PDB3|2codA:483-574PDB3|1btkA:4-133 PDB3|1b55A:4-133 PDB3|1bwnB:4-133PDB3|1unqA:6-108 PDB3|1unpA:6-108 PDB3|1h10A:6-108PDB3|1unrA:6-108 PDB3|1btn :2199-2304 PDB3|1mph :2199-2304PDB3|1wjmA:2219-2328 PDB3|1dro :2148-2259 PDB3|1v88A:149-265PDB3|1wgqA:1303-1398 PDB3|2cocA:605-703 PDB3|2cofA:354-447PDB3|2coaA:398-478 PDB3|1x1fA:26-121 PDB3|1fhoA:349-451PDB3|1ym7D:559-652 PDB3|1omwA:559-652 PDB3|2bcjA:559-652PDB3|1bak :559-652 PDB3|1pmsA:444-546 PDB3|1dbhA:444-546PDB3|1awe :444-546 PDB3|1xdvB:444-546 PDB3|1xd4A:444-546PDB3|1ki1D:1463-1571 PDB3|1zc3B:174-273 PDB3|1zc4D:174-273PDB3|1ntyA:1421-1532 PDB3|1rj2D:706-821 PDB3|1kzgC:831-946PDB3|1lb1C:831-946 PDB3|1kz7C:831-946 PDB3|1mai :22-130PDB3|1foeE:1261-1395

Pleckstrin homology domain (PH domain) 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 cytoskeletoncite journal |author=Baltimore D, Mayer BJ, Ren R, Clark KL |title=A putative modular domain present in diverse signaling proteins |journal=Cell |volume=73 |issue=4 |pages=629–630 |year=1993 |pmid=8500161 |doi=10.1016/0092-8674(93)90244-K] cite journal |author=Hemmings BA,Haslam RJ, Koide HB |title=Pleckstrin domain homology |journal=Nature |volume=363 |issue=6427 |pages=309–310 |year=1993 |pmid=8497315 |doi=10.1038/363309b0] cite journal |author=Gibson T, Musacchio A, Thompson J, Saraste M, Rice P |title=The PH domain: a common piece in the structural patchwork of signalling proteins |journal=Trends Biochem. Sci. |volume=18 |issue=9 |pages=343–348 |year=1993 |pmid=8236453 |doi=10.1016/0968-0004(93)90071-T] cite journal |author=Gibson TJ,Musacchio A, Saraste M, Hyvonen M, Birney E |title=PH domain: the first anniversary |journal=Trends Biochem. Sci. |volume=19 |issue=9 |pages=349–353 |year=1994 |pmid=7985225 |doi=10.1016/0968-0004(94)90108-2] cite journal |author=Pawson T |title=Protein modules and signalling networks |journal=Nature |volume=373 |issue=6515 |pages=573–580 |year=1995 |pmid=7531822 |doi=10.1038/373573a0] cite journal |author=Hemmings BA, Ingley E |title=Pleckstrin homology (PH) domains in signal transduction |journal=J. Cell. Biochem. |volume=56 |issue=4 |pages=436–443 |year=1994 |pmid=7890802 |doi=10.1002/jcb.240560403] cite journal |author=Saraste M, Hyvonen M |title=Pleckstrin homology domains: a fact file |journal=Curr. Opin. Struct. Biol. |volume=5 |issue=3 |pages=403–408 |year=1995 |pmid=7583640 |doi=10.1016/0959-440X(95)80104-9] .

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 compartment 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 phospho-lipid products.

tructure

The 3D structure of several PH domains has been determinedcite journal |author=Riddihough G |title=More meanders and sandwiches |journal=Nat. Struct. Biol. |volume=1 |issue=11 |pages=755–757 |year=1994 |pmid=7634082 |doi=10.1038/nsb1194-755] . 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, 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. 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 is one of the rare proteins to contain two 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 like guanine nucleotide releasing factor GNRP (Ras-GRF) (which contains 2 PH domains), guanine nucleotide exchange proteins like vav, dbl, SoS and "Saccharomyces cerevisiae" CDC24, GTPase activating proteins like rasGAP and BEM2/IPL2, and the human break point cluster protein bcr.
* 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.
* Mammalian phosphatidylinositol-specific phospholipase C (PI-PLC) (see InterPro|IPR000909) isoforms gamma and delta. Isoform gamma contains two PH domains, the second one is split into two parts separated by about 400 residues.
* Oxysterol binding proteins OSBP, S. cerevisiae OSH1 and YHR073w.
* Mouse protein citron, a putative rho/rac effector that binds to the GTP-bound forms of rho and rac.
*Several S. cerevisiae proteins involved in cell cycle regulation and bud formation like BEM2, BEM3, BUD4 and the BEM1-binding proteins BOI2 (BEB1) and BOI1 (BOB1). * C. elegans protein MIG-10.

ubfamilies

*Spectrin/pleckstrin-like InterPro|IPR001605

Human proteins containing PH domain

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; 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;

ee also

* Pleckstrin
* The unrelated FYVE domain binds Phosphatidylinositol 3-phosphate and has been found in over 60 proteins.

References

External links

* [http://www.expasy.org/cgi-bin/nicedoc.pl?PDOC50003 PH domain] in PROSITE
* [http://smart.embl-heidelberg.de/smart/do_annotation.pl?&DOMAIN=ph PH domain entry in the SMART database]
* [http://nashlab.bsd.uchicago.edu/index.php?option=com_content&task=view&id=82&Itemid=29 Nash Lab Protein Interaction Domains - PH domain description]
* - Calculated orientations of PH domains in membranes