Pleckstrin homology domain

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Federal government websites often end in. The site is secure. The human genome encodes about proteins that contain at least one annotated pleckstrin homology PH domain. As the first phosphoinositide binding module domain to be discovered, the PH domain recruits diverse protein architectures to cellular membranes. PH domains constitute one of the largest protein superfamilies, and have diverged to regulate many different signaling proteins and modules such as Dbl homology DH and Tec homology TH domains. The ligands of approximately 70 PH domains have been validated by binding assays and complexed structures, allowing meaningful extrapolation across the entire superfamily. In addition to the linear sequence motifs which are employed for phosphoinositide recognition, the three dimensional structural features that allow peripheral membrane domains to approach and insert into the bilayer are pinpointed and can be predicted ab initio.

Pleckstrin homology domain

Letunic et al. Pleckstrin homology PH domains are small modular domains that occur in a large variety of proteins. 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. PH domains have been found to possess inserted domains such as in PLC gamma, syntrophins and to be inserted within other domains. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids. 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. There are no totally invariant residues within the PH domain. This tree includes only several representative species. The complete taxonomic breakdown of all proteins with PH domain is also avaliable. Click on the protein counts, or double click on taxonomic names to display all proteins containing PH domain in the selected taxonomic class. Primary literature is listed below; Automatically-derived, secondary literature is also avaliable. The three-dimensional structure of the calponin homology domain present in many actin binding cytoskeletal and signal-transducing proteins has been determined at 2. The inositol phosphate metabolism network has been found to be much more complex than previously thought, as more and more inositol phosphates and their metabolizing enzymes have been discovered.

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.

Pleckstrin homology domain PH domain or PHIP is a protein domain of approximately amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. Individual PH domains possess specificities for phosphoinositides phosphorylated at different sites within the inositol ring, e. 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.

Federal government websites often end in. The site is secure. Pleckstrin-2 is a member of pleckstrin family with well-defined structural features that was first identified in Over the past 20 years, our understanding of PLEK2 biology has been limited to cell spreading. Recently, increasing evidences support that PLEK2 plays important roles in other cellular events beyond cell spreading, such as erythropoiesis, tumorigenesis and metastasis. It serves as a potential diagnostic and prognostic biomarker as well as an attractive target for the treatment of cancers. Herein, we summary the protein structure and molecular interactions of pleckstrin-2, with an emphasis on its regulatory roles in tumorigenesis. Pleckstrin was first initially described as a prominent substrate of protein kinase C PKC in hematopoietic cells.

Pleckstrin homology domain

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Di Paolo, G. However, these sites actually interact directly with the kinase domain that they are known to regulate, although we cannot formally exclude the possibility that lipids may also bind transiently here within the cell. J Cell Sci. Interpro abstract IPR : Pleckstrin homology PH domains are small modular domains that occur in a large variety of proteins. Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains. Please note that proteins can be included in multiple pathways, ie. The second observation derived from this genome-wide analysis of PH domains is that the number of PH domains that bind membranes is far greater than those that do not. Discrepancies between the experimental and computational results occurred where MODA falsely predicted that a PH structure did not bind membranes 10 cases or predicted a membrane-binding domain where experimental data argued otherwise 3 cases. A mass spectrometry study of proteins pulled down by PIPs immobilized on agarose beads identified PIP-binding proteins in the human proteome, but only 33 PH domain-containing proteins were found among them 32 ; while powerful, the lack of membrane environment for the PIPs in this method may present a limitation. Western blot signals were quantified by densitometry to generate the relative ratios of RhoA pulled down active and RhoA in lysates total. Acknowledgements We thank Dr. This surface includes the position of the X-linked immunodeficiency mutation in the Btk PH domain and may serve as a ligand-binding surface. Through the following examples, we inspect the consistency of predictions of membrane binding across the family.

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Alternatively, this binding might play a more direct role in membrane scission by dynamin. However, we found the vast majority of the 67 PH domains to contain this motif, with no distinction between those that bound PIPs and those that did not Supplementary Fig. Split pleckstrin homology domain-mediated cytoplasmic-nuclear localization of PI3-kinase enhancer GTPase. Anyone you share the following link with will be able to read this content:. In total, the September release of the Uniprot database contained annotated PH domains in approximately distinct human proteins. It is believed that different species of phospholipids may cooperate in the membrane to determine specific interaction with proteins 2 , 3. PH-domain-driven targeting of collybistin but not Cdc42 activation is required for synaptic gephyrin clustering. Cell 30 , — Sequence similarity was found to a putative Ras GTPase activating protein and a human interferon-gamma binding protein both in the PH domain and the Btk motif region. Menetrey J. Perhaps one of the biggest challenges for understanding the general properties of this large class of domains is to determine whether the frequently observed low-affinity and promiscuous phosphoinositide binding has functional importance. Specificity and commonality of the phosphoinositide-binding proteome analyzed by quantitative mass spectrometry. PtdIns5 P has been reported to bind specifically to the PHD for p lant h omeo d omain zinc fingers of the nuclear candidate tumor suppressor ING2 [ 62 ] and a plant trithorax homolog [ 63 ]. A putative modular domain present in diverse signaling proteins. Blue: binding; white: no binding.