Summary: PH domain
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This is the Wikipedia entry entitled "Domain of unknown function". More...
Domain of unknown function Edit Wikipedia article
A domain of unknown function (DUF) is a protein domain that has no characterised function. These families have been collected together in the Pfam database using the prefix DUF followed by a number, with examples being DUF2992 and DUF1220. There are now over 3,000 DUF families within the Pfam database representing over 20% of known families.[1]
Contents
History
The DUF naming scheme was introduced by Chris Ponting, through the addition of DUF1 and DUF2 to the SMART database.[2] These two domains were found to be widely distributed in bacterial signaling proteins. Subsequently, the functions of these domains were identified and they have since been renamed as the GGDEF domain and EAL domain respectively.
Structure
Structural genomics programmes have attempted to understand the function of DUFs through structure determination. The structures of over 250 DUF families have been solved.[3] This work showed that about two thirds of DUF families had a structure similar to a previously solved one and therefore likely to be divergent members of existing protein superfamilies, whereas about one third possessed a novel protein fold.
Frequency and conservation
More than 20% of all protein domains were annotated as DUFs in 2013. About 2,700 DUFs are found in bacteria compared with just over 1,500 in eukaryotes. Over 800 DUFs are shared between bacteria and eukaryotes, and about 300 of these are also present in archaea. A total of 2,786 bacterial Pfam domains even occur in animals, including 320 DUFs.[4]
Role in biology
Many DUFs are highly conserved, indicating an important role in biology. However, many such DUFs are not essential, hence their biological role often remains unknown. For instance, DUF143 is present in most bacteria and eukaryotic genomes.[5] However, when it was deleted in Escherichia coli no obvious phenotype was detected. Later it was shown that the proteins that contain DUF143, are ribosomal silencing factors that block the assembly of the two ribosomal subunits.[5] While this function is not essential, it helps the cells to adapt to low nutrient conditions by shutting down protein biosynthesis. As a result, these proteins and the DUF only become relevant when the cells starve.[5] It is thus believed that many DUFs (or proteins of unknown function, PUFs) are only required under certain conditions.
Essential DUFs (eDUFs)
Goodacre et al. identified 238 DUFs in 355 essential proteins (in 16 model bacterial species), most of which represent single-domain proteins, clearly establishing the biological essentiality of DUFs. These DUFs are called "essential DUFs" or eDUFs.[4]
External links
References
- ^ Bateman A, Coggill P, Finn RD (October 2010). "DUFs: families in search of function". Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 66 (Pt 10): 1148–52. PMC 2954198
. PMID 20944204. doi:10.1107/S1744309110001685. - ^ Schultz J, Milpetz F, Bork P, Ponting CP (May 1998). "SMART, a simple modular architecture research tool: identification of signaling domains". Proc. Natl. Acad. Sci. U.S.A. 95 (11): 5857–64. PMC 34487 . PMID 9600884. doi:10.1073/pnas.95.11.5857.
- ^ Jaroszewski L, Li Z, Krishna SS, et al. (September 2009). "Exploration of uncharted regions of the protein universe". PLoS Biol. 7 (9): e1000205. PMC 2744874 . PMID 19787035. doi:10.1371/journal.pbio.1000205.
- ^ a b c Goodacre, N. F.; Gerloff, D. L.; Uetz, P. (2013). "Protein Domains of Unknown Function Are Essential in Bacteria". MBio. 5 (1): e00744–e00713. PMC 3884060 . PMID 24381303. doi:10.1128/mBio.00744-13.
- ^ a b c Häuser, R.; Pech, M.; Kijek, J.; Yamamoto, H.; Titz, B. R.; Naeve, F.; Tovchigrechko, A.; Yamamoto, K.; Szaflarski, W.; Takeuchi, N.; Stellberger, T.; Diefenbacher, M. E.; Nierhaus, K. H.; Uetz, P. (2012). Hughes, Diarmaid, ed. "RsfA (YbeB) Proteins Are Conserved Ribosomal Silencing Factors". PLoS Genetics. 8 (7): e1002815. PMC 3400551 . PMID 22829778. doi:10.1371/journal.pgen.1002815.
This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.
This is the Wikipedia entry entitled "Pleckstrin homology domain". More...
Pleckstrin homology domain Edit Wikipedia article
PH domain of tyrosine-protein kinase BTK
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| Identifiers | |||||||||
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| Symbol | PH | ||||||||
| Pfam | PF00169 | ||||||||
| InterPro | IPR001849 | ||||||||
| SMART | PH | ||||||||
| PROSITE | PDOC50003 | ||||||||
| SCOP | 1dyn | ||||||||
| SUPERFAMILY | 1dyn | ||||||||
| OPM superfamily | 51 | ||||||||
| OPM protein | 1pls | ||||||||
| CDD | cd00821 | ||||||||
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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 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.
Contents
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 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 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 S. 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.
- Ceramide kinase, a lipid kinase that phosphorylates ceramides to ceramide-1-phosphate.[13]
Subfamilies
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, 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.
References
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Riddihough G (November 1994). "More meanders and sandwiches". Nature Structural Biology. 1 (11): 755–7. doi:10.1038/nsb1194-755. PMID 7634082.
- ^ 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.
- ^ 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.
External links
- Nash Lab Protein Interaction Domains - PH domain description
- UMich Orientation of Proteins in Membranes families/superfamily-51 - Calculated orientations of PH domains in membranes
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Internal database links
| SCOOP: | PH |
Domain organisation
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Pfam Clan
This family is a member of clan PH (CL0266), which has the following description:
Members of this clan share a PH-like fold. Many families in this clan bind to short peptide motifs in proteins and are involved in signalling.
The clan contains the following 71 members:
BBL5 bPH_1 bPH_2 bPH_3 bPH_4 bPH_5 bPH_6 CARM1 Carm_PH DCP1 DUF1126 DUF1681 DUF3203 EbsA FERM_C Glycoprot_B_PH1 Glycoprot_B_PH2 GRAM hSac2 ICAP-1_inte_bdg INPP5B_PH IQ_SEC7_PH IRS ISP1_C ISP3_C Jak1_Phl Mcp5_PH Myosin_TH1 OCRL_clath_bd PH PH_10 PH_11 PH_12 PH_13 PH_14 PH_15 PH_16 PH_17 PH_18 PH_2 PH_3 PH_4 PH_5 PH_6 PH_8 PH_9 PH_BEACH PH_RBD PH_TFIIH PID PID_2 POB3_N Proteasom_Rpn13 PTB Ran_BP1 Rtt106 SCAB-PH Sec3-PIP2_bind Sharpin_PH SIN1_PH SNX17_FERM_C SPT16 SSrecog SYCP2_SLD UCH_N VID27_PH Voldacs Vps36_ESCRT-II WH1 YcxB ZFYVE21_CAlignments
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
| Seed (9) |
Full (185) |
Representative proteomes | UniProt (260) |
NCBI (456) |
Meta (0) |
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| RP15 (35) |
RP35 (82) |
RP55 (150) |
RP75 (178) |
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| PP/heatmap | 1 | ||||||||
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
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| Seed (9) |
Full (185) |
Representative proteomes | UniProt (260) |
NCBI (456) |
Meta (0) |
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| RP15 (35) |
RP35 (82) |
RP55 (150) |
RP75 (178) |
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| Raw Stockholm | |||||||||
| Gzipped | |||||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
Trees
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
Curation
| Seed source: | PRODOM:PD041151 |
| Previous IDs: | DUF5369; |
| Type: | Domain |
| Sequence Ontology: | SO:0000417 |
| Author: |
El-Gebali S  , Bateman A
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| Number in seed: | 9 |
| Number in full: | 185 |
| Average length of the domain: | 93.50 aa |
| Average identity of full alignment: | 43 % |
| Average coverage of the sequence by the domain: | 56.25 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 107 | ||||||||||||
| Family (HMM) version: | 2 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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