Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Triads”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 217 records · Page 12Linked to original sources
PubMed2002

An unusual case of complete Carney's triad in a 14-year-old boy.

Carney's triad represents the association of gastric gastrointestinal stromal tumor, pulmonary chondroma, and extraadrenal paraganglioma. Only 79 cases of this rare condition have been described. Here, the authors describe the unusual case of a 14-year-old boy who presented with a complete Carney's triad. This is only the second reported case in the world literature of a patient manifesting a complete Carney's triad at presentation. The management of each tumor is discussed.

Abdominal Neoplasms↗
PubMed1988

[The Currarino triad--a study of 4 cases].

Report on 4 cases of a rare syndrome known as Currarino triad. The features of this triad consist of constipation, anorectal malformations, presacral masses and a curved defect of the os sacrum (scimitar defect). Currarino was the first to detect autosomal-dominant hereditary transmission in about 50 per cent of the patients. Each congenital or chronic constipation should prompt an early radiological examination including x-ray films of the os sacrum and the anorectum to exclude or to find a Currarino triad. The finding of a "scimitar sacrum" makes it essential to perform a contrast enema of the anorectum and a CT of the pelvic structures in the patient and his family. The possibilities of management depending on the nature of the presacral masses and their communication to the rectum and/or to the spinal channel are described. It is emphasised that a subtitle division of the rectal and spinal tissues has to be the first aim of operation to prevent a dangerous and life-threatening infection of the meningeal sac.

Adolescent↗
PubMed2003

Deletion of histidine triad nucleotide-binding protein 1/PKC-interacting protein in mice enhances cell growth and carcinogenesis.

PKC-interacting protein (PKCI), also designated histidine triad nucleotide-binding protein 1, belongs to the histidine triad (HIT) family of proteins. Its structure is highly conserved from bacteria to humans and shares homology with the tumor-suppressor gene fragile histidine triad (FHIT). Although it was originally thought to inhibit PKC, its actual physiologic function is not known. Therefore, we used the technique of homologous recombination to generate homozygous deleted PKCI-/- mice. These mice display normal fetal and adult development. However, when mouse embryo fibroblasts were established from 13.5-day embryos and serially passaged the PKCI-/- cells displayed an increase in growth rate and underwent spontaneous immortalization, whereas the PKCI+/+ cells senesced and ceased growing. Furthermore, the PKCI-/- mouse embryo fibroblasts displayed increased resistance to cytotoxicity by ionizing radiation. In view of these findings we examined possible effects of PKCI on susceptibility to carcinogenicity. Both PKCI+/+ and PKCI-/- mice were treated with the chemical carcinogen N-nitrosomethylbenzylamine (NMBA) by intragastric administration and killed 12 weeks later. As expected with this protocol, NMBA induced squamous tumors (both papillomas and carcinomas) of the forestomach. The incidence, multiplicity per mouse, volume, and degree of malignancy of these tumors were significantly greater in the PKCI-/- than in the PKCI+/+ mice. Furthermore, four adenomas and one adenocarcinoma of the glandular stomach were found in the NMBA-treated PKCI-/- mice but no tumors of the glandular stomach were found in the NMBA-treated PKCI+/+ mice or in any of the untreated mice. Taken together, these findings suggest that, like FHIT, PKCI may normally play a tumor-suppressor role. The possible role of PKCI as a tumor suppressor in humans remains to be determined.

Animals↗
PubMed2000

The structure of aspartyl dipeptidase reveals a unique fold with a Ser-His-Glu catalytic triad.

The three-dimensional structure of Salmonella typhimurium aspartyl dipeptidase, peptidase E, was solved crystallographically and refined to 1.2-A resolution. The structure of this 25-kDa enzyme consists of two mixed beta-sheets forming a V, flanked by six alpha-helices. The active site contains a Ser-His-Glu catalytic triad and is the first example of a serine peptidase/protease with a glutamate in the catalytic triad. The active site Ser is located on a strand-helix motif reminiscent of that found in alpha/beta-hydrolases, but the polypeptide fold and the organization of the catalytic triad differ from those of the known serine proteases. This enzyme is a member of a family of serine hydrolases and appears to represent a new example of convergent evolution of peptidase activity.

Catalytic Domain↗
PubMed1993

Breaching the conformational integrity of the catalytic triad of the serine protease plasmin: localized disruption of a side chain of His-603 strongly inhibits the amidolytic activity of human plasmin.

Site-directed mutagenesis has been used to construct a cDNA that encodes a recombinant variant human plasminogen (hPg) containing a Pro-611-->Ile mutation (MrhPg). The mutein was expressed in recombinant baculovirus-infected Spodoptera frugiperda cells (IPLB-SF-21AE), and purified. After activation of this zymogen to its corresponding form of the serine protease plasmin (MrhPm), this latter enzyme was essentially inactive toward an amide plasmin substrate, most likely from alteration of the spatial relationships of the active-site His-603 to its partners of the catalytic triad, Asp-646 and Ser-741. Partial amidolytic activity of MrhPm was restored as a consequence of imidazole addition to the assay medium, due to an increase in the catalytic constant kcat of the enzyme. The serine protease inhibitor, diisopropylphosphofluoridate, when preincubated with MrhPm, did not inhibit restoration of its amidolytic activity with imidazole, whereas diisopropylphosphofluoridate did inhibit the amidolytic activity of MrhPm in the presence of imidazole. This result implies that His-603 directly influences the nucleophilic character of Ser-741. When imidazole as pretreated with alpha-N-tosyl-L-lysine chloromethyl ketone, the ability of this imidazole solution to restore amidolytic activity to MrhPm was eliminated, suggesting that N alpha-(p-tosyl)lysine chloromethyl ketone directs into the binding pocket a derivatized form of imidazole, which is ineffective as an His-603 substitute. These results indicate that the conformational reorientation of His-603 results in a malfunctional catalytic triad in the serine protease MrhPm, thus leading to an inactive enzyme despite the presence of all three essential amino acids of the catalytic triad. Addition of extramolecular imidazole restores a portion of the amidolytic activity of this mutant enzyme. These data also argue for an enzyme mechanism in which the active-center His-603 residue directly influences the nucleophilicity of the active-site Ser 741 residue.

Amino Acid Sequence↗
PubMed2001

Structural plasticity of an invariant hydrophobic triad in the switch regions of Rab GTPases is a determinant of effector recognition.

Rab GTPases function as regulatory components of an evolutionarily conserved machinery that mediates docking, priming, and fusion of vesicles with intracellular membranes. We have previously shown that the active conformation of Rab3A is stabilized by a substantial hydrophobic interface between the putative conformational switch regions (Dumas, J. J., Zhu, Z., Connolly, J. L., and Lambright, D. G. (1999) Structure 7, 413-423). A triad of invariant hydrophobic residues at this switch interface (Phe-59, Trp-76, and Tyr-91) represents a major interaction determinant between the switch regions of Rab3A and the Rab3A-specific effector Rabphilin3A (Ostermeier, C., and Brunger, A. T. (1999) Cell 96, 363-374). Here, we report the crystal structure of the active form of Rab5C, a prototypical endocytic Rab GTPase. As is true for Rab3A, the active conformation of Rab5C is stabilized by a hydrophobic interface between the switch regions. However, the conformation of the invariant hydrophobic triad (residues Phe-58, Trp-75, and Tyr-90 in Rab5C) is dramatically altered such that the resulting surface is noncomplementary to the switch interaction epitope of Rabphilin3A. This structural rearrangement reflects a set of nonconservative substitutions in the hydrophobic core between the central beta sheet and the alpha2 helix. These observations demonstrate that structural plasticity involving an invariant hydrophobic triad at the switch interface contributes to the mechanism by which effectors recognize distinct Rab subfamilies. Thus, the active conformation of the switch regions conveys information about the identity of a particular Rab GTPase as well as the state of the bound nucleotide.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Evidence for distinct roles in catalysis for residues of the serine-serine-lysine catalytic triad of fatty acid amide hydrolase.

Fatty acid amide hydrolase (FAAH) is a mammalian amidase signature enzyme that inactivates neuromodulatory fatty acid amides, including the endogenous cannabinoid anandamide and the sleep-inducing substance oleamide. The recent determination of the three-dimensional structures of FAAH and two distantly related bacterial amidase signature enzymes indicates that these enzymes employ an unusual serine-serine-lysine triad for catalysis (Ser-241/Ser-217/Lys-142 in FAAH). Mutagenesis of each of the triad residues in FAAH has been shown to severely reduce amidase activity; however, how these residues contribute, both individually and in cooperation, to catalysis remains unclear. Here, through a combination of site-directed mutagenesis, enzyme kinetics, and chemical labeling experiments, we provide evidence that each FAAH triad residue plays a distinct role in catalysis. In particular, the mutation of Lys-142 to alanine indicates that this residue functions as both a base involved in the activation of the Ser-241 nucleophile and an acid that participates in the protonation of the substrate leaving group. This latter property appears to support the unusual ability of FAAH to hydrolyze amides and esters at equivalent rates. Interestingly, although structural evidence indicates that the impact of Lys-142 on catalysis probably occurs through the bridging Ser-217, the mutation of this latter residue to alanine impaired catalytic activity but left the amide/ester hydrolysis ratios of FAAH intact. Collectively, these findings suggest that FAAH possesses a specialized active site structure dedicated to a mechanism for competitive amide and ester hydrolysis where nucleophile attack and leaving group protonation occur in a coordinated manner dependent on Lys-142.

Amidohydrolases↗
PubMed2004

Expression cloning and demonstration of Enterococcus faecalis lipoamidase (pyruvate dehydrogenase inactivase) as a Ser-Ser-Lys triad amidohydrolase.

Enterococcus faecalis lipoamidase was discovered almost 50 years ago (Reed, L. J., Koike, M., Levitch, M. E., and Leach, F. R. (1958) J. Biol. Chem. 232, 143-158) as an enzyme activity that cleaved lipoic acid from small lipoylated molecules and from pyruvate dehydrogenase thereby inactivating the enzyme. Although the partially purified enzyme was a key reagent in proving the crucial role of protein-bound lipoic acid in the reaction mechanism of the 2-oxoacid dehydrogenases, the identity of the lipoamidase protein and the encoding gene remained unknown. We report isolation of the lipoamidase gene by screening an expression library made in an unusual cosmid vector in which the copy number of the vector is readily varied from 1-2 to 40-80 in an appropriate Escherichia coli host. Although designed for manipulation of large genome segments, the vector was also ideally suited to isolation of the gene encoding the extremely toxic lipoamidase. The gene encoding lipoamidase was isolated by screening for expression in E. coli and proved to encode an unexpectedly large protein (80 kDa) that contained the sequence signature of the Ser-Ser-Lys triad amidohydrolase family. The hexa-histidine-tagged protein was expressed in E. coli and purified to near-homogeneity. The purified enzyme was found to cleave both small molecule lipoylated and biotinylated substrates as well as lipoic acid from two 2-oxoacid dehydrogenases and an isolated lipoylated lipoyl domain derived from the pyruvate dehydrogenase E2 subunit. Lipoamidase-mediated inactivation of the 2-oxoacid dehydrogenases was observed both in vivo and in vitro. Mutagenesis studies showed that the residues of the Ser-Ser-Lys triad were required for activity on both small molecule and protein substrates and confirmed that lipoamidase is a member of the Ser-Ser-Lys triad amidohydrolase family.

Amidohydrolases↗
PubMed2006

Aprataxin forms a discrete branch in the HIT (histidine triad) superfamily of proteins with both DNA/RNA binding and nucleotide hydrolase activities.

Ataxia with oculomotor apraxia type 1 (AOA1) is an early onset autosomal recessive spinocerebellar ataxia with a defect in the protein Aprataxin, implicated in the response of cells to DNA damage. We describe here the expression of a recombinant form of Aprataxin and show that it has dual DNA binding and nucleotide hydrolase activities. This protein binds to double-stranded DNA with high affinity but is also capable of binding double-stranded RNA and single-strand DNA, with increased affinity for hairpin structures. No increased binding was observed with a variety of DNA structures mimicking intermediates in DNA repair. The DNA binding observed here was not dependent on zinc, and the addition of exogenous zinc abolished DNA binding. We also demonstrate that Aprataxin hydrolyzes with similar efficiency the model histidine triad nucleotide-binding protein substrate, AMPNH2, and the Fragile histidine triad protein substrate, Ap4A. These activities were significantly reduced in the presence of duplex DNA and to a lesser extent in the presence of single-strand DNA, and removal of the N-terminal Forkhead associated domain did not alter activity. Finally, comparison of sequence relationships between the histidine triad superfamily members shows that Aprataxin forms a distinct branch in this superfamily. In addition to its capacity for nucleotide binding and hydrolysis, the observation that it also binds DNA and RNA adds a new dimension to this superfamily of proteins and provides further support for a role for Aprataxin in the cellular response to DNA damage.

DNA↗
PubMed2006

Lysyl-tRNA synthetase-generated lysyl-adenylate is a substrate for histidine triad nucleotide binding proteins.

Histidine triad nucleotide binding proteins (Hints) are the most ancient members of the histidine triad protein superfamily of nucleotidyltransferases and hydrolyases. Protein-protein interaction studies have found that complexes of the transcription factors MITF or USF2 and lysyl-tRNA synthetase (LysRS) are associated with human Hint1. Therefore, we hypothesized that lysyl-AMP or the LysRS.lysyl-AMP may be a native substrate for Hints. To explore the biochemical relationship between Hint1 and LysRS, a series of catalytic radiolabeling, mutagenesis, and kinetic experiments was conducted with purified LysRSs and Hints from human and Escherichia coli. After incubation of the E. coli or human LysRS with Hints and [alpha-(32)P]ATP, but not [alpha-(32)P]GTP, (32)P-labeled Hints were observed. By varying time and the concentrations of lysine, Mg(2+), or LysRS, the adenylation of Hint was found to be dependent on the formation of lysyl-AMP. Site-directed mutagenesis studies of the active site histidine triad revealed that Hint labeling could be abolished by substitution of either His-101 of E. coli hinT or His-112 of human Hint1 by either alanine or glycine. Ap(4)A, believed to be synthesized by LysRS in vivo, and Zn(2+) were shown to inhibit the formation of Hint-AMP with an IC(50) value in the low micromolar range. Consistent with pyrophosphate being an inhibitor for aminoacyl-tRNA synthetase, incubations in the presence of pyrophosphatase resulted in enhanced formation of Hint-AMP. These results demonstrate that the lysyl-AMP intermediate formed by LysRS is a natural substrate for Hints and suggests a potential highly conserved regulatory role for Hints on LysRS and possibly other aminoacyl-tRNA synthetases.

Adenosine Monophosphate↗
PubMed2006

Complete familial Currarino triad in association with Hirschsprung's disease: magnetic resonance imaging features and the spectrum of anorectal malformations.

Currarino syndrome, a rare hereditary condition, is defined as a partial sacral agenesis associated with a presacral mass and anorectal malformation. The authors present two siblings with complete Currarino triad and their mother with incomplete triad. The complete Currarino triad in the older sibling was associated with Hirschsprung's disease as the second reported case in the literature. Anorectal malformations, whether suspected of Currarino syndrome or not, should be examined with lumbosacral magnetic resonance imaging.

Abnormalities, Multiple↗
PubMed2004

Thrombogenesis, atherogenesis and angiogenesis in vascular disease: a new 'vascular triad'.

Amongst the components of the pathophysiology of atherosclerosis are the tendency to thrombus formation (i.e., thrombogenesis) and the loss of endothelial cell integrity. The endothelium is also implicated in atherogenesis, as vasa vasorum are present in the adventitia and media at a higher density in atherosclerotic tissue, and that neovascularisation leading to collateral growth bypassing obstruction and/or stenoses provides important alternative routes to feeding distal tissues. The development of these new blood vessels is the process of angiogenesis. The present 'viewpoint' article will explore the relationships between the three processes. There is considerable evidence that atherogenesis and thrombogenesis are intimately linked, but angiogenesis in cardiovascular disease is a recently developed concept. We propose a new 'vascular triad' of these abnormal pathophysiological processes, leading to an alternative view of the pathogenesis of vascular disease. Indeed, we suggest that angiogenesis is an important aspect of the pathophysiology of cardiovascular disease, impacting with both thrombogenesis and atherogenesis, in a new vascular triad (the 'Birmingham vascular triad').

Arteriosclerosis↗
PubMed1996

Formation of triads without the dihydropyridine receptor alpha subunits in cell lines from dysgenic skeletal muscle.

Muscular dysgenesis (mdg/mdg), a mutation of the skeletal muscle dihydropyridine receptor (DHPR) alpha 1 subunit, has served as a model to study the functions of the DHPR in excitation-contraction coupling and its role in triad formation. We have investigated the question of whether the lack of the DHPR in dysgenic skeletal muscle results in a failure of triad formation, using cell lines (GLT and NLT) derived from dysgenic (mdg/mdg) and normal (+/+) muscle, respectively. The lines were generated by transfection of myoblasts with a plasmid encoding a Large T antigen. Both cell lines express muscle-specific proteins and begin organization of sarcomeres as demonstrated by immunocytochemistry. Similar to primary cultures, dysgenic (GLT) myoblasts show a higher incidence of cell fusion than their normal counterparts (NLT). NLT myotubes develop spontaneous contractile activity, and fluorescent Ca2+ recordings show Ca2+ release in response to depolarization. In contrast, GLTs show neither spontaneous nor depolarization-induced Ca2+ transients, but do release Ca2+ from the sarcoplasmic reticulum (SR) in response to caffeine. Despite normal transverse tubule (T-tubule) formation, GLT myotubes lack the alpha 1 subunit of the skeletal muscle DHPR, and the alpha 2 subunit is mistargeted. Nevertheless, the ryanodine receptor (RyR) frequently develops its normal, clustered organization in the absence of both DHPR alpha subunits in the T-tubules. In EM, these RyR clusters correspond to T-tubule/SR junctions with regularly spaced feet. These findings provide conclusive evidence that interactions between the DHPR and RyR are not involved in the formation of triad junctions or in the normal organization of the RyR in the junctional SR.

Animals↗
PubMed2001

Deficiency of triad junction and contraction in mutant skeletal muscle lacking junctophilin type 1.

In skeletal muscle excitation-contraction (E-C) coupling, the depolarization signal is converted from the intracellular Ca2+ store into Ca2+ release by functional coupling between the cell surface voltage sensor and the Ca2+ release channel on the sarcoplasmic reticulum (SR). The signal conversion occurs in the junctional membrane complex known as the triad junction, where the invaginated plasma membrane called the transverse-tubule (T-tubule) is pinched from both sides by SR membranes. Previous studies have suggested that junctophilins (JPs) contribute to the formation of the junctional membrane complexes by spanning the intracellular store membrane and interacting with the plasma membrane (PM) in excitable cells. Of the three JP subtypes, both type 1 (JP-1) and type 2 (JP-2) are abundantly expressed in skeletal muscle. To examine the physiological role of JP-1 in skeletal muscle, we generated mutant mice lacking JP-1. The JP-1 knockout mice showed no milk suckling and died shortly after birth. Ultrastructural analysis demonstrated that triad junctions were reduced in number, and that the SR was often structurally abnormal in the skeletal muscles of the mutant mice. The mutant muscle developed less contractile force (evoked by low-frequency electrical stimuli) and showed abnormal sensitivities to extracellular Ca2+. Our results indicate that JP-1 contributes to the construction of triad junctions and that it is essential for the efficiency of signal conversion during E-C coupling in skeletal muscle.

Animals↗
PubMed2005

Performance of the log-linear approach to case-parent triad data for assessing maternal genetic associations with offspring disease: type I error, power, and bias.

Maternal genetic variation may serve as a biomarker in studies aimed at clarifying fetal determinants of infant or adult disease. The log-linear approach to case-parent triad data (LCPT) can be used to investigate maternal genetic polymorphisms in relation to offspring disease risk, but LCPT operating characteristics have been reported for only a limited range of situations. The authors performed a simulation study to investigate the performance of the LCPT for assessing maternal associations with offspring disease risk over a wide range of scenarios with varying sample sizes (n), high-risk allele frequencies (f ), and modes of inheritance, all of which greatly affect the expected number of triads in informative categories. For most f values less than 0.5, the LCPT approach with 200 triads allowed for approximately 80% power to detect valid, unbiased maternal relative risks of 2 when inheritance was log-additive or dominant. When inheritance was recessive, this was true for most f 's greater than 0.35. Outside of this range, however, power and bias depended greatly on the mode of inheritance, f, and n. On the basis of these findings, epidemiologists may consider the LCPT a useful approach for assessing maternal relative risks unless one expects a very rare or fairly common maternal allele to increase offspring disease risk.

Bias↗
PubMed2002

Structure of malonamidase E2 reveals a novel Ser-cisSer-Lys catalytic triad in a new serine hydrolase fold that is prevalent in nature.

A large group of hydrolytic enzymes, which contain a conserved stretch of approximately 130 amino acids designated the amidase signature (AS) sequence, constitutes a super family that is distinct from any other known hydrolase family. AS family enzymes are widespread in nature, ranging from bacteria to humans, and exhibit a variety of biological functions. Here we report the first structure of an AS family enzyme provided by the crystal structure of malonamidase E2 from Bradyrhizobium japonicum. The structure, representing a new protein fold, reveals a previously unidentified Ser-cisSer-Lys catalytic machinery that is absolutely conserved throughout the family. This family of enzymes appears to be evolutionarily distinct but has diverged to acquire a wide spectrum of individual substrate specificities, while maintaining a core structure that supports the catalytic function of the unique triad. Based of the structures of the enzyme in two different inhibited states, an unusual action mechanism of the triad is proposed that accounts for the role of the cis conformation in the triad.

Amidohydrolases↗
PubMed2003

Intergenerational triads in grandparent-headed families.

OBJECTIVES: Grandparents are becoming caregivers of their grandchildren more often as a result of their adult children's drug addiction, mental problems, and financial need. This study examined grandmothers' well-being in relation to bonding within intergenerational triads consisting of grandmother, parent, and grandchild. METHODS: Interviews were conducted with 987 grandmothers recruited through schools and media, including 512 custodial grandmothers raising their grandchildren and 475 coparenting grandmothers helping their adult sons or daughters to raise their grandchildren. RESULTS: Contrary to expectation, triangulation involving a weak parent-grandmother relationship was not related to significantly lower grandmother well-being. In contrast, the emotionally isolated parent, particularly common in custodial families, was related to lower grandmother well-being, whether or not the parent lived in the household. The configuration in which the parent provided a link for both other generations was frequent in coparenting families, but it was not significantly different in grandmother well-being compared to other linking triads. DISCUSSION: Intergenerational triad types appear to be broadly relevant emotional configurations that transcend living situations but appear with different frequencies in custodial and coparenting families. Results affirm the utility of examining multirelationship patterns and describe the restructuring of intergenerational relationships characteristic of parental absence.

Aged↗
PubMed2005

Functional roles of carboxylate residues comprising the DNA polymerase active site triad of Ty3 reverse transcriptase.

Aspartic acid residues comprising the -D-(aa) n -Y-L-D-D- DNA polymerase active site triad of reverse transcriptase from the Saccharomyces cerevisiae long terminal repeat-retrotransposon Ty3 (Asp151, Asp213 and Asp214) were evaluated via site-directed mutagenesis. An Asp151-->Glu substitution showed a dramatic decrease in catalytic efficiency and a severe translocation defect following initiation of DNA synthesis. In contrast, enzymes harboring the equivalent alteration at Asp213 and Asp214 retained DNA polymerase activity. Asp151-->Asn and Asp213-->Asn substitutions eliminated both polymerase activities. However, while Asp214 of the triad could be replaced by either Asn or Glu, introducing Gln seriously affected processivity. Mutants of the carboxylate triad at positions 151 and 213 also failed to catalyze pyrophosphorolysis. Finally, alterations to the DNA polymerase active site affected RNase H activity, suggesting a close spatial relationship between these N- and C-terminal catalytic centers. Taken together, our data reveal a critical role for Asp151 and Asp213 in catalysis. In contrast, the second carboxylate of the Y-L-D-D motif (Asp214) is not essential for catalysis, and possibly fulfills a structural role. Although Asp214 was most insensitive to substitution with respect to activity of the recombinant enzyme, all alterations at this position were lethal for Ty3 transposition.

Amino Acid Substitution↗