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• W2063708626 abstract "The GTP binding Gαh (transglutaminase II) mediates the α1B-adrenoreceptor signal to a 69-kDa phospholipase C (PLC). Thus, Gαh possesses both GTPase and transglutaminase activities with a signal transfer role. The recognition sites of this unique GTP binding protein for either the receptor or the effector are completely unknown. A site on human heart Gαh (hhGαh) has been identified that interacts with and stimulates PLC. Expressed mutants of hhGαh with deleted C-terminal regions lost the response to(-)-epinephrine and GTP and failed to coimmunoprecipitate PLC by the specific Gh7α antibody. The interaction regions were further defined by studies with synthetic peptides of hhGαh and a chimera in which residues Val665-Lys672 of hhGαh were substituted with Ile707-Ser714 residues of human coagulation factor XIIIa. Thus, eight amino acid residues near the C terminus of hhGαh are critical for recognition and stimulation of PLC. The GTP binding Gαh (transglutaminase II) mediates the α1B-adrenoreceptor signal to a 69-kDa phospholipase C (PLC). Thus, Gαh possesses both GTPase and transglutaminase activities with a signal transfer role. The recognition sites of this unique GTP binding protein for either the receptor or the effector are completely unknown. A site on human heart Gαh (hhGαh) has been identified that interacts with and stimulates PLC. Expressed mutants of hhGαh with deleted C-terminal regions lost the response to(-)-epinephrine and GTP and failed to coimmunoprecipitate PLC by the specific Gh7α antibody. The interaction regions were further defined by studies with synthetic peptides of hhGαh and a chimera in which residues Val665-Lys672 of hhGαh were substituted with Ile707-Ser714 residues of human coagulation factor XIIIa. Thus, eight amino acid residues near the C terminus of hhGαh are critical for recognition and stimulation of PLC. INTRODUCTIONThe Gαh protein, transglutaminase II (TGase II), 1The abbreviations used are: TGase IItransglutaminase IIFXIIIacoagulation factor XIIIaGTPgSguanosine 5′-O-(3-thiotriphosphate)PCRpolymerase chain reactionPLCphospholipase CSMsucrose monolauratehhGαhhuman heart Gαh. is unique in that the enzyme exhibits two distinct enzyme activities, namely guanosine triphosphatase (GTPase) and TGase, with a signal transfer role ((1Nakaoka H. Perez D.M. Baek K.J. Das T. Husain A. Misono K. Im M-J. Graham R.M. Science. 1994; 264: 1593-1596Crossref PubMed Scopus (528) Google Scholar); see also (2Achyuthan K.E. Greenberg C.S. J. Biol. Chem. 1987; 262: 1901-1906Abstract Full Text PDF PubMed Google Scholar) and (3Lee K.N. Birckbichler P.J. Patterson M.K. Biochem. Biophys. Res. Commun. 1989; 162: 1370-1375Crossref PubMed Scopus (93) Google Scholar)). The GTPase function of Gαh differs from other TGases, coagulation factor XIIIa (FXIIIa), keratinocyte, and epidermal transglutaminases (4Greenberg C.S. Birckbichler P.J. Rice R.H. FASEB J. 1991; 5: 3071-3077Crossref PubMed Scopus (927) Google Scholar). Gαh, which is species specific in molecular mass, directly interacts with α1-adrenoreceptor (5Im M.-J. Graham R.M. J. Biol. Chem. 1990; 265: 18944-18951Abstract Full Text PDF PubMed Google Scholar, 6Baek K.J. Das T. Gray C. Antar S. Murugesan G. Im M.-J. J. Biol. Chem. 1993; 268: 27390-27397Abstract Full Text PDF PubMed Google Scholar) and a 69-kDa PLC in the activation process(7Das T. Baek K.J. Gray C. Im M.-J. J. Biol. Chem. 1993; 268: 27398-27405Abstract Full Text PDF PubMed Google Scholar, 8Im M.-J. Gray C. Rim A.J. J. Biol. Chem. 1992; 267: 8887-8894Abstract Full Text PDF PubMed Google Scholar). Physiological TGase role of Gαh remains unclear(4Greenberg C.S. Birckbichler P.J. Rice R.H. FASEB J. 1991; 5: 3071-3077Crossref PubMed Scopus (927) Google Scholar). However, it has been suggested that TGase II is involved in control of cell growth and differentiation (9Birckbichler P.J. Orr G.R. Patterson Jr., M.K. Conway E. Carter H.A. Proc. Natl. Acad. Sci. U. S. A. 1981; 78: 5005-5008Crossref PubMed Scopus (106) Google Scholar, 10Murtaugh M.P. Mehta K. Johnson J. Myers M. Juliano R.L. Davis P.J.A. J. Biol. Chem. 1983; 258: 11074-11081Abstract Full Text PDF PubMed Google Scholar, 11Piacentini M. Autori F. Dini L. Farrace M.G. Ghibelli L. Piredda L. Fesus L. Cell Tissue Res. 1991; 263: 227-235Crossref PubMed Scopus (131) Google Scholar) and activation of cytosolic phospholipase A2(12Cordella-Miele E. Miele L. Mukherjee A.B. J. Biol. Chem. 1990; 265: 17180-17188Abstract Full Text PDF PubMed Google Scholar).The amino acid sequences of all TGases including Gαh show high homology in the middle portions of the polypeptides, which include the TGase active site and a calcium binding region(13Ichinose A. Bottenus R.E. Davie E.W. J. Biol. Chem. 1990; 265: 13411-13414Abstract Full Text PDF PubMed Google Scholar). However, the N- and C-terminal regions of Gαh do not share sequence homology among TGases. This divergence is particularly greater at the C-terminal domain of Gαh, giving rise to the hypothesis that this region may play a significant role in hormone signaling. In this study, evidence for a direct interaction between the region of Gαh and PLC is demonstrated. This interaction activates PLC.RESULTS AND DISCUSSIONThe isolated full-length hhGαh cDNA was an exact match in the nucleotide and deduced amino acid sequences with the human endothelial TGase II(14Genitile V. Saydak M. Chiocca E.A. Akande N. Birckbichler P.J. Lee K.N. Stein J.P. Davis P.J.A. J. Biol. Chem. 1991; 266: 478-483Abstract Full Text PDF PubMed Google Scholar). To identify interaction sites of hhGαh with the α1-adrenoreceptor and PLC, systematic 10-amino acid-deleted mutants of hhGαh cDNA(s) were generated from the C-terminal end (Fig. 1). The full-length hhGαh cDNA and truncated hhGαh cDNA(s) were cotransfected into COS-1 cells with α1B-adrenoreceptor cDNA. The expressed proteins were recognized by the Gh7a antibody as well as guinea pig TGase II antibody and were of the expected sizes with ~80 kDa for full-length hhGαh and a decrease in size as the length of nucleotide deletion increased (Fig. 2A). The α1B-receptor was also expressed, resulting in 2-3 pmol/mg protein of [3H]prazosin binding. The expressed hhGαh proteins exhibited both GTP binding and TGase activities (Fig. 2B and inset). The Ca2+-stimulated TGase activities of expressed hhGαh and its truncated mutants were completely inhibited with >100 μM GTP, and the inhibitory potency (IC50) of GTP was in the range of 20-50 μM for all hhGαh proteins, also confirming that GTP is a negative regulator for the TGase of Gαh(1Nakaoka H. Perez D.M. Baek K.J. Das T. Husain A. Misono K. Im M-J. Graham R.M. Science. 1994; 264: 1593-1596Crossref PubMed Scopus (528) Google Scholar, 3Lee K.N. Birckbichler P.J. Patterson M.K. Biochem. Biophys. Res. Commun. 1989; 162: 1370-1375Crossref PubMed Scopus (93) Google Scholar, 4Greenberg C.S. Birckbichler P.J. Rice R.H. FASEB J. 1991; 5: 3071-3077Crossref PubMed Scopus (927) Google Scholar).Figure 2:A, an autoradiogram of an immunoblot of the expressed membrane proteins from COS-1 cells transfected with hhGαh or mutant hhGαh polypeptides using polyclonal Gh7a antibody. Molecular sizes (in kilodaltons) are shown on the left. Endogenous Gαh (TGase II) is seen in the membranes from expressed α1B-receptor (α1B-AR) alone and mutants. The protein expression level was ~4-10-fold higher than the endogenous Gαh. B, the GTP-mediated inhibition of TGase activities of the expressed hhGαh and mutants. The inhibition of TGase activity (50 ng/tube) was determined with GTP in the presence of 0.1 mM [3H]putrescine, 1% N,N‘-dimethyl casein, 0.5 mM CaCl2, and 2 mM MgCl2 in HSD buffer at 30°C for 30 min. The inset shows the stimulation of TGase (50 ng/tube) in the presence of 0.5 mM CaCl2 without GTP under the same conditions. The results are the mean of three independent experiments performed in duplicate.View Large Image Figure ViewerDownload Hi-res image Download (PPT)All mutants, as well as hhGαh, elevated the basal PLC activity as compared to that of the α1B-receptor alone (Fig. 3A), indicating induction of precoupled protein complexes resulting from overexpression of the proteins(1Nakaoka H. Perez D.M. Baek K.J. Das T. Husain A. Misono K. Im M-J. Graham R.M. Science. 1994; 264: 1593-1596Crossref PubMed Scopus (528) Google Scholar, 18Coupry I. Duzic E. Lanier S.M. J. Biol. Chem. 1992; 267: 9852-9857Abstract Full Text PDF PubMed Google Scholar). The(-)-epinephrine-mediated activation of PLC was increased approximately 2-fold with hhGαh and the ΔK676 mutant, whereas the ΔL656 and ΔE646 mutants lost the agonist-mediated PLC stimulation, exhibiting a level similar to that of the α1B-receptor alone. The ΔN666 mutant stimulated PLC upon activation of the α1-receptor, but to a lesser extent than wild type. These data suggested that a region comprising 20 amino acids between His657 and Lys677 is critical for coupling to the α1B-receptor or PLC.Figure 3:Coupling ability of expressed hhGαh and its mutants. A, epinephrine-stimulated inositol 1,4,5-triphosphate (IP3) accumulation in membranes from COS-1 cells coexpressed with α1B-receptor and hhGαh or its mutants. The α1-receptor-mediated PLC stimulation was determined after normalizing receptor number (100 fmol/tube) in a 100-μl final volume. Receptor number was normalized, since the receptor number is the determinant in signal manipulation, not G-protein number(17May D.C. Ross E.M. Biochemistry. 1988; 27: 4888-4893Crossref PubMed Scopus (17) Google Scholar), and the expression level of hhGαh and its mutants was also 3-5-fold higher than the receptor level. The results are the mean ± S.E. of three independent experiments performed in duplicate. α1B-AR, α1B-adrenoreceptor; Ep, (-)-epinephrine; Ph, phentolamine. B, remaining α1B-adrenoreceptor in the supernatants after coimmunoprecipitation with hhGαh and its mutants using Gh7a antibody-protein A-agarose. The α1-adrenoreceptor absorbed to preimmune protein A-agarose was less than 5% as compared to the resin-untreated samples. The preimmune-resin-treated samples were taken as 100% for each sample. C, immunoadsorption of a complex of PLC with hhGαh and its mutants by Gh7a antibody-protein A-agarose. The PLC activity absorbed to preimmune protein A-agarose was negligible and taken as nonspecific binding. The data shown are the mean ± S.E. of three independent experiments in triplicate.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The possibility that the receptor and/or PLC recognition sites were deleted was examined by coimmunoprecipitation. The mutants, ΔK676, ΔN666, and ΔL656, coexpressed with the α1B-adrenoreceptor, coimmunoprecipitated >90%α1-receptor as wild type did, indicating that the receptor interaction site on these mutants was intact (Fig. 3B). However, the mutant, ΔE646, consistently coimmunoprecipitated less receptor (~80%) than other mutants but more than the receptor alone (~35%). Although less coimmunoprecipitation of the receptor with this mutant suggested that this region on hhGαh might contain the receptor interaction site, this point should be further investigated. Coimmunoprecipitation of the receptor with membrane extract from the expressed α1B-receptor alone was probably due to complex formation between the internal Gαh and the receptor.The loss of PLC interaction site was then assessed by coimmunoprecipitation (Fig. 3C). The results revealed that the ΔK676 mutant coimmunoprecipitated PLC as effectively as the wild type, whereas the ΔL656 and ΔE646 mutants failed to coimmunoprecipitate PLC, showing a similar level to that of the α1B-receptor alone. The ΔL666 mutant again showed lower coimmunoprecipitation of PLC than hhGαh but higher than theΔL656 and ΔE646 mutants. The loss of the PLC interaction site was further confirmed by determining PLC stimulation in response to GTP (Fig. 4, A and B). As expected, the basal levels of PLC in membranes expressing hhGαh and mutants were increased 3~6-fold compared to the α1B-receptor alone. Within these increases, the PLC basal activity gradually decreased as the deletion size increased (Fig. 4A). In the presence of GTP, the expressed hhGαh and the mutant ΔK676 increased PLC stimulation 2-fold (Fig. 4B). Increases in deletion size also resulted in a gradual decrease of GTP-mediated PLC stimulation. Mutants ΔL656 and ΔE646 lost ability to stimulate PLC in response to GTP. These results were consistent with the finding from the coimmunoprecipitation studies and strongly suggested that a region between His657 and Lys677 on hhGαh contained a PLC interaction site.Figure 4:The GTP-mediated PLC activation. The membranes (30 μg/tube) were preincubated with and without 0.1 mM GTP in the presence of 2 mM MgCl2 at 30°C for 30 min. Production of IP3 was measured with various concentrations of CaCl2 at 30°C for 10 min. Panels A and B are shown in the absence and presence of GTP, respectively. The data shown are the mean ± S.E. of three independent experiments in duplicate.View Large Image Figure ViewerDownload Hi-res image Download (PPT)To further define this putative PLC interaction site, four overlapping peptides corresponding to the deleted regions of hhGαh were synthesized and tested for their ability to inhibit coimmunoprecipitation of PLC (Fig. 5A). Peptide 4 (Leu661-Lys672), among the four peptides, was able to inhibit coimmunoprecipitation of PLC (Fig. 5B). Coimmunoprecipitation of PLC was inhibited in a concentration-dependent manner, and at 100-200 μM of the peptide, the inhibition reached ~80%, suggesting that other interaction site(s) probably exist (Fig. 5C). The competition potency (IC50) of peptide 4 for the interaction between hhGαh and PLC was ~20 μM.Figure 5:A, map of the synthesized peptides of hhGαh. Overlapping amino acids in peptides 3 and 4 are indicated with asterisks. B, effect of peptides of hhGαh on coimmunoprecipitation of PLC by Gh7a antibody-protein A-agarose. The membrane extracts (100 μg/tube) were preincubated with 100 μM peptide and subjected to immunoprecipitation. PLC activity was determined as detailed under “Experimental Procedures.” The results are a mean ± S.E. of three independent experiments performed in duplicate. C, competition of peptide 4 with hhGαh to coimmunoprecipitate PLC by Gh7a antibody-protein A-agarose. The experiments were performed with various concentrations of peptide 4 under the same conditions as detailed under “Experimental Procedures.” The data presented are a mean of the duplicated experiments using three independently expressed proteins.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The findings that a region of 12 amino acids between Leu661 and Lys672 in hhGαh contains a PLC interaction site were refined by a chimera, hhGαh/FXIIIa, in which eight amino acid residues Val665-Lys672 of hhGαh were substituted with the corresponding region (Ile707-Ser714) of human factor XIIIa (see Fig. 1)(13Ichinose A. Bottenus R.E. Davie E.W. J. Biol. Chem. 1990; 265: 13411-13414Abstract Full Text PDF PubMed Google Scholar). This region of FXIIIa was chosen because FXIIIa does not interact with or stimulate PLC or bind GTP(4Greenberg C.S. Birckbichler P.J. Rice R.H. FASEB J. 1991; 5: 3071-3077Crossref PubMed Scopus (927) Google Scholar), and this region of FXIIIa is distinct among TGases(13Ichinose A. Bottenus R.E. Davie E.W. J. Biol. Chem. 1990; 265: 13411-13414Abstract Full Text PDF PubMed Google Scholar). The chimera was expressed ~7-fold higher than endogenous Gαh and to the similar level of hhGαh (Fig. 6A). The chimera protein exhibited GTP binding and TGase activity at the same levels as the wild type (Fig. 6B). In addition, using the partially purified chimera when the GTP-mediated inhibition of TGase activity was titrated, the inhibition was similar to ΔK676 and wild type, indicating that substitution of this region did not change GTP binding affinity (data not shown). The chimera also failed to stimulate PLC in response to GTP (Fig. 6C) and upon activation of the α1B-receptor (data not shown). The Ga antibody did not coimmunoprecipitate PLC but effectively coimmunoprecipitated the receptor (data not shown). These findings clearly demonstrate that the C-terminal region of hhGαh from Val665 to Lys672 is a critical site for interaction and stimulation of PLC.Figure 6:Coupling ability of the expressed hhGαh/FXIIIa chimera. A, an autoradiogram of an immunoblot of the expressed membrane proteins from COS-1 cells transfected with α1-adrenoreceptor alone or with wild-type or hhGαh/FXIIIa chimera. α1B-AR, α1B-adrenoreceptor; WT, hhGαh; Chi, hhGαh/FXIIIa chimera. B, TGase and GTP binding activity of the expressed wild-type or hhGαh/FXIIIa chimera in the membranes. Both enzyme activities were determined in the presence or absence of 0.1 mM GTP as detailed in Fig. 2B. C, GTP-mediated PLC stimulation. The PLC activity was measured using the membranes (30 μg/tube) in the presence of 0.1 mM GTP, 2 mM MgCl2, and 10 μM CaCl2 under the conditions detailed under “Experimental Procedures.” The results are the mean ± S.E. of three independent experiments performed in duplicate. IP3, inositol 1,4,5-triphosphate.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The substituted region of the chimera has a significant change in properties of the amino acids (Fig. 1). Thus, four charged amino acids (Asn667, Glu669, Asp671, and Lys672) were substituted for serine, except Asp671. Hydrophobic amino acids (Val665, Val666, and Phe668) were also changed to smaller (V666A and F668M) or larger (V665I) amino acids. Although it has been suggested that replacement of a bulky side chain of hydrophobic amino acids can result in loss of activity due to unfavorable van der Waals interactions(19Eriksson A.E. Baase W.E. Zhang X.J. Heinz D.W. Blaber M. Baldwin E.P. Science. 1992; 255: 178-183Crossref PubMed Scopus (882) Google Scholar), overall hydrophobicity of the substituted amino acids, however, remains similar. Therefore, it is unlikely that a hydrophobic interaction is responsible for coupling of hhGαh to PLC. Three charged amino acids in this region, i.e. a hydrophilic interaction, probably play a critical role in the contact of hhGαh with PLC.In heterotrimeric G-protein-mediated signaling systems, the near C-terminal domain of the α-subunit appears to contain an effector contact region (adenylyl cyclase with GαS(20Masters S.B. Sullivan K.A. Miller R.T. Beiderman B. Lopez N.G. Ramachandran J. Bourne H.R. Science. 1988; 241: 448-451Crossref PubMed Scopus (104) Google Scholar, 21Itoh H. Gilman A.G. J. Biol. Chem. 1991; 266: 16226-16231Abstract Full Text PDF PubMed Google Scholar, 22Berlot C.H. Bourne H.R. Cell. 1992; 68: 911-922Abstract Full Text PDF PubMed Scopus (160) Google Scholar) and cGMP-phosphodiesterase with Gαt(23Rarick H.M. Artemyev N.O. Hamm H.E. Science. 1992; 256: 1031-1033Crossref PubMed Scopus (92) Google Scholar)). Despite extensive primary structural differences between Gαh and α-subunits of the heterotrimeric G-proteins, our data indicate that Gαh seems to share this common structural feature in signaling. Our data also suggest that the carboxyl domain of Gαh with its primary structure distinct from other transglutaminases is likely to be involved in signaling functions, including receptor and GTP binding sites. INTRODUCTIONThe Gαh protein, transglutaminase II (TGase II), 1The abbreviations used are: TGase IItransglutaminase IIFXIIIacoagulation factor XIIIaGTPgSguanosine 5′-O-(3-thiotriphosphate)PCRpolymerase chain reactionPLCphospholipase CSMsucrose monolauratehhGαhhuman heart Gαh. is unique in that the enzyme exhibits two distinct enzyme activities, namely guanosine triphosphatase (GTPase) and TGase, with a signal transfer role ((1Nakaoka H. Perez D.M. Baek K.J. Das T. Husain A. Misono K. Im M-J. Graham R.M. Science. 1994; 264: 1593-1596Crossref PubMed Scopus (528) Google Scholar); see also (2Achyuthan K.E. Greenberg C.S. J. Biol. Chem. 1987; 262: 1901-1906Abstract Full Text PDF PubMed Google Scholar) and (3Lee K.N. Birckbichler P.J. Patterson M.K. Biochem. Biophys. Res. Commun. 1989; 162: 1370-1375Crossref PubMed Scopus (93) Google Scholar)). The GTPase function of Gαh differs from other TGases, coagulation factor XIIIa (FXIIIa), keratinocyte, and epidermal transglutaminases (4Greenberg C.S. Birckbichler P.J. Rice R.H. FASEB J. 1991; 5: 3071-3077Crossref PubMed Scopus (927) Google Scholar). Gαh, which is species specific in molecular mass, directly interacts with α1-adrenoreceptor (5Im M.-J. Graham R.M. J. Biol. Chem. 1990; 265: 18944-18951Abstract Full Text PDF PubMed Google Scholar, 6Baek K.J. Das T. Gray C. Antar S. Murugesan G. Im M.-J. J. Biol. Chem. 1993; 268: 27390-27397Abstract Full Text PDF PubMed Google Scholar) and a 69-kDa PLC in the activation process(7Das T. Baek K.J. Gray C. Im M.-J. J. Biol. Chem. 1993; 268: 27398-27405Abstract Full Text PDF PubMed Google Scholar, 8Im M.-J. Gray C. Rim A.J. J. Biol. Chem. 1992; 267: 8887-8894Abstract Full Text PDF PubMed Google Scholar). Physiological TGase role of Gαh remains unclear(4Greenberg C.S. Birckbichler P.J. Rice R.H. FASEB J. 1991; 5: 3071-3077Crossref PubMed Scopus (927) Google Scholar). However, it has been suggested that TGase II is involved in control of cell growth and differentiation (9Birckbichler P.J. Orr G.R. Patterson Jr., M.K. Conway E. Carter H.A. Proc. Natl. Acad. Sci. U. S. A. 1981; 78: 5005-5008Crossref PubMed Scopus (106) Google Scholar, 10Murtaugh M.P. Mehta K. Johnson J. Myers M. Juliano R.L. Davis P.J.A. J. Biol. Chem. 1983; 258: 11074-11081Abstract Full Text PDF PubMed Google Scholar, 11Piacentini M. Autori F. Dini L. Farrace M.G. Ghibelli L. Piredda L. Fesus L. Cell Tissue Res. 1991; 263: 227-235Crossref PubMed Scopus (131) Google Scholar) and activation of cytosolic phospholipase A2(12Cordella-Miele E. Miele L. Mukherjee A.B. J. Biol. Chem. 1990; 265: 17180-17188Abstract Full Text PDF PubMed Google Scholar).The amino acid sequences of all TGases including Gαh show high homology in the middle portions of the polypeptides, which include the TGase active site and a calcium binding region(13Ichinose A. Bottenus R.E. Davie E.W. J. Biol. Chem. 1990; 265: 13411-13414Abstract Full Text PDF PubMed Google Scholar). However, the N- and C-terminal regions of Gαh do not share sequence homology among TGases. This divergence is particularly greater at the C-terminal domain of Gαh, giving rise to the hypothesis that this region may play a significant role in hormone signaling. In this study, evidence for a direct interaction between the region of Gαh and PLC is demonstrated. This interaction activates PLC." @default.
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• W2063708626 title "Interaction Site of GTP Binding Gh (Transglutaminase II) with Phospholipase C" @default.
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