Pleckstrin homology

Ferguson, K.M., et al. Structure of the high affinity complex of inositol triphosphate with a phospholipase C pleckstrin homology domain. Celt 83 1037-1046, 1995. 

All PLC isozymes have conserved catalytic domains designated X and Y, and a C2 domain similar to that in cPLA2 (Fig. 2). In addition, the (3, y and 8 isozymes have pleckstrin homology (PH) domains and EF-hand domains located in theN-teiminal region. The y isozymes differ in that they have Src homology domains (SH2 and SH3) and an additional PH domain split by the SH domains. The (3 and y isozymes are of140-155 kDa mass, whereas the 8 isozymes are smaller (85 kDa) and the o isozyme is larger (240 kDa). 

Pleckstrin homology domain (PH-domain) was first identified at the amino and carboxyl termini of a haematopoietic protein called pleckstrin. PH-domain, a protein region of approximately 120 amino acids, by binding to phosphatidylinositol lipids of the biological membranes induces the translocation of the PH-domain containing protein to membrane compartment. Various PH-domains possess specificities for phosphoinositides phosphorylated at different sites within the inositol ring. 

PH Pleckstrin homology domain Binding to membrane phospholipids, such as phosphoinositides... 

Platinum Complexes Pleckstrin Homology Domain Plexins PMF... 

The major 3 -phosphoinositide products of class I PI3Ks are phosphati-dylinositol 3,4,5-trisphosphate [PI(3,4,5)P3, which is formed primarily from phosphorylation of PI(4,5)P2) and its metabolite phosphatidylinositol 3,4-bisphosphate, PI(3,4)P2]. The basal levels of PI(3,4)P2 and PI(3,4,5)P3 in cells are usually in low abundance but can rise sharply after cell stimulation to interact with an array of protein effectors via pleckstrin homology (PH) domains, modular segments of about 100 amino acids found in many signaling proteins. It is these PH-domain-containing proteins that are able to propagate and drive downstream signaling events. 

Lemmon MA, Ferguson KM. Signal-dependent membrane targeting by pleckstrin homology (PH) domains. Biochem J 2000 350(Pt 1) 1—18. 

Protein kinase B, or Akt, was discovered as the product of an oncogene of the acutely transforming retrovirus AKT8, causing T-cell lymphomas in mice. It encodes a fusion product of a cellular serine/threonine protein kinase and the viral structural protein Gag. This kinase is similar to both protein kinase Ce (PKCe 73% identity to the catalytic domain) and protein kinase A (PKA 68%). It differs from other protein kinases in that it contains a pleckstrin homology (PH) domain, which allows it to bind to polyphosphoinositide head groups (and also to G-protein fly subunits). To date, three subtypes have been identified a, (3, and y, all of which show a broad tissue distribution. It... 

Proton-driven spin diffusion Pulsed field gradient spin-echo Pleckstrin homology Poly(hydroxyethylmethacrylate)... 

Membrane associations can occur by selective protein binding to lipid head groups. One example is spectrin, which binds to phosphatidylinositol-4,5-bisphosphate by means of a pleckstrin-homology (PH) domain [5] (Fig. 2-5). and also to phosphatidyl serine [6] (Fig. 2-6). 

Lietzke, S. E., Bose, S., Cronin, T. et al. Structural basis of 3-phosphoinositide recognition by pleckstrin homology domains. Mol. Cell 6 385-394,2000. 

Despite the similar functions of each isozyme, only two regions of amino acid homology exist (X and Y), one of 150 and a second of 120 amino acid residues, which are 54% and 42% identical among the isozymes but are differentially localized within each enzyme (Fig. 20-3). The X and Y domains form the catalytic core of the enzyme. A characteristic of the (3 and 8 isoforms is that relatively few amino acids (40-110) separate the X and Y entities, whereas a much larger separation is observed for the PLCy isoform (approx. 400). In addition, in PLCy, the region between X and Y contains amino acid sequences that are found in nonreceptor tyrosine kinases (SH2 and SH3 domains). All four isoforms possess pleckstrin homology (PH) domains. The latter are considered to enable the enzyme to become tethered to the plasmalemma via an interaction with PI(4,5)P2. In addition, all PLC isoforms possess an E-F hand domain, which is located between PH and X domains, and a C2 domain, which is located close to the Y domain. 

C2, protein kinase C domain ENTH, epsin N-terminal homology FERM, band 4.1,exrin, radixin, moesin FYVE, Fabl, YOTB, Vacl, EEA1 MARCKS, myristoylated alanine-rich protein kinase C substrate PH, pleckstrin homology. 

Gompounds that inhibit Akt-1 are of increasing interest as possible oncology therapeutics [59]. Akt-1 is a multi-domain protein that is known to be activated after binding of its pleckstrin homology (PH) domain to its endogenous target. A report from researchers at Merck indicates that their Akt-1 inhibitor does... 

R. G., Huber, H.E. Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors. 

Takeuchi H, Kanematsu T, Misumi Y, et al. Distinct specificity in the binding of inositol phosphates by pleckstrin homology domains of pleckstrin, RAC-protein kinase, diacylglycerol kinase and a new 130 kDa protein. Biochem Biophys Acta 1997 1359(3) 275-285. 

The structural element of PARK that interacts specifically with the Py-complex is localized in the C-terminal third of the PARK seqimce (Inglese et al., 1994). It possesses the characteristics of an independently folding protein domain and is ranked with the pleckstrin homology domains (PH domains). The PH domains are protein modules (see Chapter 8), foimd in many proteins, that by binding of inositol lipids (see Chapter 6) mediate protein-membrane interactions. 

The central function of Ptdlns(3,4,5)P3 is to bind to pleckstrin homology domains (PH domains) of signal proteins. PH domains are found as independent protein modules in many signal proteins (see Chapter 8.2.4) that mediate protein-lipid and possibly also protein-protein interactions. Ptdlns(3,4,5)P3 formed by P13-kinase serves to recruit signal molecules next in sequence to the membrane and to involve them in signal conduction. In addition, Ptdlns(3,4,5)P3 can also bring about an allosteric activation of its effector proteins. 

Fig. 8.9. Crosslinking of signal proteins with the help of protein modnles. A hypothetical protein is shown which contains SH2, SH3, PTB and PH domains. Recognition of phosphotyrosine residues occurs with the help of SH2 or PTB domains SH3 domains bind to proline-rich sequences (Pro in Protein 3) whilst the pleckstrin homology domains (PH domains) mediate binding to phosphatidyl-inositol-phosphates (PtdInsP) in the membrane. In an idealized scheme, the modular protein can associate several proteins (Protein 1 - Protein 3) and mediate interactions between these proteins (shown as broken arrows). The PH domain helps to recruit the complex to the cell membrane favoring interactions with other membrane-associated proteins (Protein X).

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