Pleckstrin homology domain

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.

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.

Pleckstrin homology domain

Federal government websites often end in. The site is secure. Pleckstrin homology PH domains represent the 11 th most common domain in the human proteome. Cases in which PH domains bind specific phosphoinositides with high affinity are restricted to those phosphoinositides that have a pair of adjacent phosphates in their inositol headgroup. One group of PH domains appears to bind both phosphoinositides with little specificity and Arf family small G-proteins, and are targeted to the Golgi apparatus where both phosphoinositides and the relevant Arfs are both present. Here, the PH domains may function as coincidence detectors. A central challenge in understanding the majority of PH domains to establish whether the very low affinity phosphoinositide binding reported in many cases has any functional relevance. For PH domains from dynamin and from Dbl family proteins, this weak binding does appear to be functionally important, although its precise mechanistic role is unclear. In many other cases, it is quite likely that alternative binding partners are more relevant, and that the observed PH domain homology represents conservation of structural fold rather than function. Pleckstrin Homology PH domains were first pointed out as regions of approximately amino acids that share sequence similarity with two such regions in pleckstrin [ 1 , 2 ], a major substrate of protein kinase C in platelets [ 3 ]. A key role for such interactions in cell signaling was revealed when certain PH domains were found to be recruited transiently to the plasma membrane following activation of phosphoinositide 3-kinase signaling pathways by a wide array of cell surface agonists [ 10 , 11 ]. Our understanding of how certain PH domains bind specific phosphoinositides with high affinity has thus become quite sophisticated, both at structural and functional levels [ 15 , 16 ].

Alignment and Conservation Protein sequences that contain at least one PH domain were selected from the curated SwissProt database. Sensitive tools to detect and allow the characterization of even weakly binding domains are needed to understand the execution and regulation of cellular events. Pleckstrin homology domain B.

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Here we employ a single-molecule pulldown assay to study interactions of lipid vesicles with full-length proteins in mammalian whole cell lysates. Twenty predicted binders and 11 predicted non-binders are assayed, yielding results highly consistent with the prediction.

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. The analysis shows that conserved structural surfaces distinguish which PH domains associate with membrane from those that do not. Moreover, the results indicate that lipid-binding PH domains can be classified into different functional subgroups based on the type of membrane insertion elements they project towards the bilayer. The pleckstrin homology PH domain was discovered 22 years ago in various proteins including pleckstrin which are involved in signaling, cytoskeletal organization, membrane trafficking and phospholipid processing [ 1 , 2 ].

Pleckstrin homology domain

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.

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For instance, the membrane binding site of ADAP was co-crystallized with a phosphoinositide headgroup [ 56 ] but was not predicted to bind bilayers by MODA. This is consistent with the idea that the protein expressed in bacteria may lack either a necessary post-translational modification or a co-factor. Solution structure of the PH domain of pleckstrin homology domain-containing protein family A member 5 from human. Our assay uses small unilamellar vesicles that mimic the composition of cell membranes, which are commonly employed to study lipid—protein interactions. Joe Troy for help with the initial identification of PH domain sequences, and Ms. Given the high likelihood that the PH domains mediate PIP binding of the full-length proteins, we compared the sequences of the PH domains of the 67 proteins we studied plus AKT1-PH as a positive control, excluding the four proteins that bound lipids non-specifically. Figure 3. Weak binding may not be detected by most techniques and therefore, when the analysis is carried out, a genuine transient or non-specific membrane binding domain may be regarded as a non-binder, introducing a bias towards PH domains that are tight binders or required a specific lipid ligand. Genome-wide analysis of membrane targeting by S. Pleckstrin homology PH domains are small modular domains that occur in a large variety of proteins. Trends Biochem Sci.

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Tools Tools. Oncogene 33 , — Evolution species in which this domain is found Taxonomic distribution of proteins containing PH domain. Domain involved in Ras-like GTPase signalling. All data generated or analyzed during this study are included in the manuscript, its supplementary information, and source data file, and from the corresponding author upon reasonable request. Proton, nitrogen, and carbon chemical shift assignments have been made for the SH2 domain of Grb2. Bravo, J. Residues possibly involved in ligand binding are in apparently flexible loops. For instance, the use of dot-blots or PIP strips on complex surfaces generates results which do not necessarily agree with solution data from NMR, fluorescence data with modified proteins, or surface plasmon resonance SPR data from sensor chips. The three-dimensional fold of the Grb2 SH2 domain is similar to that observed for other SH2 domains and consists of two alpha-helical segments and eight beta-strands, six strands that make up two contiguous antiparallel beta-sheets, and two strands that form two short parallel beta-sheets. More generally, it has to be considered that the common fold observed for the PH domain structures solved so far does not necessarily mean that all PH domains have similar functions. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. The structure is monomeric, in contrast to the well-defined intimate dimerization of the crystal structure of this molecule. Each vertical black line represents one PH domain.