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At least 163 records · Page 9Linked to original sources
PubMed1978

The precise and entire antigenic structure of lysozyme: implications of surface-simulation synthesis and the molecular features of protein antigenic sites.

Intensive research in the author's laboratory over a 10-year period has now culminated in the precise determination of the entire antigenic structure of native hen egg-white lysozyme. The protein carries three antigenic sites. Each site is made up of spatially adjacent surface residues that are not in direct peptide linkage. The residues of each site describe an imaginary line which circumscribes part of the surface topography of the protein and act functionally towards the antibody as if they are in direct peptide bond linkage. The reactivity of each site is fully satisfied by an appropriate surface-simulation synthetic peptide, and the three synthetic sites account for the full immunochemical reactivity of the native protein. Each site is subject to conformational restrictions and exhibits directionality which is a function of side chain orientations. The antigenic sites of myoglobin and lysozyme are compared. It is proposed that antigenic sites of the type found in myoglobin are called "continuous sites", while antigenic sites of the type seen in lysozyme are defined as "discontinuous sites".

Amino Acid Sequence↗
PubMed1990

The molecular features of membrane perturbation by anaesthetic steroids: a study using differential scanning calorimetry, small angle X-ray diffraction and solid state 2H NMR.

We have studied the interactions of the anaesthetic steroid alphaxalone and its inactive isomer delta 16-alphaxalone with model membrane bilayers using differential scanning calorimetry, small angle X-ray diffraction and solid state NMR. Our data show that the anaesthetic steroid broadens the membrane phase transition and increases the ratio of gauche to trans conformers in the membrane. Delta 16-Alphaxalone has only small effects on membrane and incorporates to a limited degree in the bilayer. The amphipathic anaesthetic steroid alphaxalone is located near the membrane interface (the junction of the polar and hydrophobic regions of the phospholipids forming the bilayer). It orients with its long axis parallel to the chains of the lipid membranes and its 3 alpha-hydroxyl group near the sn-2 carbonyl. Anchoring of the steroid at the membrane interface and imperfect packing with the bilayer chains may be involved in membrane perturbation and eventually lead to anaesthesia.

Anesthetics↗
PubMed2001

Genetic and molecular features of Su(P), a gene that interacts with ref(2)P in male fertility of Drosophila melanogaster.

The ref(2)P gene is involved in the control of sigma rhabdovirus multiplication in Drosophila melanogaster. ref(2)P activity is also necessary for male fertility. However, in one-third of laboratory strains tested, males that lacked ref(2)P activity were fertile. In all such strains studied, the male sterility phenotype was abolished due to the presence of a particular allele at the Su(P) locus, at 73B1-2. These spontaneous suppressor alleles were dominant. We were able to induce dominant suppressor alleles at the Su(P) locus by X-ray mutagenesis and hybrid dysgenesis, suggesting that null alleles of Su(P) confer the dominant suppressor phenotype. The Su(P) gene was cloned by P element tagging. The P element-tagged alleles identified a Su(P) transcript as a 1.4-kb mRNA produced in the soma of both males and females, which is also abundant in ovaries.

Alleles↗
PubMed1996

Chronic myeloid leukemia of thrombocythemic onset: a CML subtype with distinct hematological and molecular features?

Among 84 consecutive patients with chronic phase Ph-positive chronic myeloid leukemia (CML) who were investigated for the hybrid BCR/ABL mRNA, in six cases (7%) the disease mimicked essential thrombocythemia (ET) at presentation, because of marked thrombocytosis (platelet counts ranging from 1003 x 10(9)/l to 2800 x 10(9)/l) and moderate leukocytosis (WBC counts from 10 x 10(9)/l to 19 x 10(9)/l). At initial examination, four of the six patients showed a few (4-9%) immature myeloid cells in the peripheral blood, and two had blood basophilia. All six patients later developed increasing leukocytosis, and two subsequently died from blast crisis and accelerated CML, respectively. In the overall series, 38 patients (45%) expressed the b2a2 type of BCR/ABL mRNA, and 46 (55%) either the b3a2 or both mRNAs. By contrast, only one of the six patients with CML of thrombocythemic onset expressed the b2a2 mRNA vs five with either b3a2 (n = 4) or both mRNA types (n = 1). The above results, in conjunction with similar data from a few previously published cases, suggest an association between the above form of CML and b3a2 type of BCR/ABL transcript.

Adolescent↗
PubMed2005

Structure and dynamics of the human pleckstrin DEP domain: distinct molecular features of a novel DEP domain subfamily.

Pleckstrin1 is a major substrate for protein kinase C in platelets and leukocytes, and comprises a central DEP (disheveled, Egl-10, pleckstrin) domain, which is flanked by two PH (pleckstrin homology) domains. DEP domains display a unique alpha/beta fold and have been implicated in membrane binding utilizing different mechanisms. Using multiple sequence alignments and phylogenetic tree reconstructions, we find that 6 subfamilies of the DEP domain exist, of which pleckstrin represents a novel and distinct subfamily. To clarify structural determinants of the DEP fold and to gain further insight into the role of the DEP domain, we determined the three-dimensional structure of the pleckstrin DEP domain using heteronuclear NMR spectroscopy. Pleckstrin DEP shares main structural features with the DEP domains of disheveled and Epac, which belong to different DEP subfamilies. However, the pleckstrin DEP fold is distinct from these structures and contains an additional, short helix alpha4 inserted in the beta4-beta5 loop that exhibits increased backbone mobility as judged by NMR relaxation measurements. Based on sequence conservation, the helix alpha4 may also be present in the DEP domains of regulator of G-protein signaling (RGS) proteins, which are members of the same DEP subfamily. In pleckstrin, the DEP domain is surrounded by two PH domains. Structural analysis and charge complementarity suggest that the DEP domain may interact with the N-terminal PH domain in pleckstrin. Phosphorylation of the PH-DEP linker, which is required for pleckstrin function, could regulate such an intramolecular interaction. This suggests a role of the pleckstrin DEP domain in intramolecular domain interactions, which is distinct from the functions of other DEP domain subfamilies found so far.

Amino Acid Sequence↗
PubMed2026

Age-stratified mutation patterns in early-onset colorectal cancer reveal distinct molecular features and therapeutic implications.

BACKGROUND: Colorectal cancer (CRC) is increasingly diagnosed in younger adults, with evidence that early-onset cases (age <50 years) differ in the spectrum of prevalent gene mutations compared with older individuals. To evaluate how these age-related differences may inform testing guidelines and therapeutic development, we examined mutation rates of the most prevalent gene mutations across four age-stratified cohorts. PATIENTS AND METHODS: Clinicogenomic data were obtained from Memorial Sloan Kettering Center for Harmonized Onco-genomic Research Dataset and China Pan-Cancer cohorts available in cBioPortal. A total of 6762 samples were analyzed. Mutation frequencies for a comprehensive panel of the 100 most prevalent CRC genes were compared across four age groups: 18-29 (n = 79), 30-39 (n = 402), 40-49 (n = 1064), and &#x2265;50 (n = 5217) using chi-square analysis. False discovery rate (FDR) correction for multiple comparisons was carried out using Benjamini-Hochberg procedure. RESULTS: Statistically significant variation in mutation frequency across age groups was seen in 22 key genes. APC mutations increased with age and were seen in 49.4% of patients in the 18-29 group, 69.7% in 30-39, 73.3% in 40-49, and 75.25% of patients &#x2265;50 (P < 0.001, FDR < 0.001). The oldest cohort was more than three times more likely to have an APC mutation than the youngest [odds ratio (OR) = 3.74, 95% confidence interval (CI) 2.44-5.74, P < 0.001]. In contrast, SMAD4 mutations were twice as common in the youngest age group at 31.6% compared with those over 40, with a prevalence of 17.29% in patients 40-49, and 18.84% in patients over 50 (OR = 2.03, 95% CI 1.26-3.27, P < 0.001, FDR < 0.001). POLE mutations peaked in the 30-39 age group with a prevalence of 10.7% compared with 6.3% in patients aged 18-29, 4.9% in patients aged 40-49, and 5.9% in patients aged &#x2265;50 (P < 0.001, FDR < 0.001). Individuals in the 30-39 group were nearly twice as likely to carry a POLE mutation compared with those over 40 (OR = 1.96, 95% CI 1.41-2.74, P < 0.001). CONCLUSIONS: Differences in mutations of key genes including a lower prevalence of APC mutations and increased SMAD4 mutations in younger individuals provides further supporting evidence that early-onset CRC may represent a distinct biological subtype of CRC. Enrichment of POLE mutations in younger patients highlights the importance of expanded molecular profiling in early-onset CRC, which could help identify patients most likely to benefit from immunotherapy and advance personalized treatment strategies in CRC. Together, these findings reinforce the need to approach early-onset CRC as a distinct biological entity and ensure that appropriate molecular assays are incorporated to guide care.

APC↗
PubMed1993

Molecular features of mollicutes.

It is now firmly established that the mollicutes are true eubacteria. They have evolved regressively (i.e., by genome reduction) from gram-positive bacterial ancestors with a low content of guanine plus cytosine in DNA--more specifically, from certain clostridia. Many of their properties, such as small genome size, small number of rRNA operons and tRNA genes, lack of a cell wall, fastidious growth, and limited metabolic activities, are seen as the result of this evolution. Other properties, such as the anaerobiosis of their earliest evolving members (anaeroplasmas and asteroleplasmas), the high adenine-plus-thymine content of their DNA, their lack of sensitivity to rifampin, and the regulatory signals for the transcription of their DNA, have been inherited from their eubacterial ancestors. However, the mollicutes are not simply wall-less gram-positive bacteria. They have properties of their own. High adenine-thymine pressure has resulted in a particular codon usage, where, for instance, UGA is read as tryptophan and not as stop. These organisms occupy unique ecological niches and have developed peculiar systems for pathogenicity, cell adhesion, antigenic variation, and (in the case of the spiroplasmas) helical morphology and motility. The putative role of certain mollicutes as cofactors in the development of AIDS may involve their mitogenicity, their superantigenicity, and their ability to induce cytokines.

Bacterial Outer Membrane Proteins↗
PubMed2002

Ascidian and amphioxus Adh genes correlate functional and molecular features of the ADH family expansion during vertebrate evolution.

The alcohol dehydrogenase (ADH) family has evolved into at least eight ADH classes during vertebrate evolution. We have characterized three prevertebrate forms of the parent enzyme of this family, including one from an urochordate (Ciona intestinalis) and two from cephalochordates (Branchiostoma floridae and Branchiostoma lanceolatum). An evolutionary analysis of the family was performed gathering data from protein and gene structures, exon-intron distribution, and functional features through chordate lines. Our data strongly support that the ADH family expansion occurred 500 million years ago, after the cephalochordate/vertebrate split, probably in the gnathostome subphylum line of the vertebrates. Evolutionary rates differ between the ancestral, ADH3 (glutathione-dependent formaldehyde dehydrogenase), and the emerging forms, including the classical alcohol dehydrogenase, ADH1, which has an evolutionary rate 3.6-fold that of the ADH3 form. Phylogenetic analysis and chromosomal mapping of the vertebrate Adh gene cluster suggest that family expansion took place by tandem duplications, probably concurrent with the extensive isoform burst observed before the fish/tetrapode split, rather than through the large-scale genome duplications also postulated in early vertebrate evolution. The absence of multifunctionality in lower chordate ADHs and the structures compared argue in favor of the acquisition of new functions in vertebrate ADH classes. Finally, comparison between B. floridae and B. lanceolatum Adhs provides the first estimate for a cephalochordate speciation, 190 million years ago, probably concomitant with the beginning of the drifting of major land masses from the Pangea.

Alcohol Dehydrogenase↗
PubMed1996

Molecular features of the TSPY gene of gibbons and Old World monkeys.

Restriction pattern, chromosome localization and the sequence of the testis-specific gene, TSPY, were investigated in the white-handed gibbon, agile gibbon, siamang, hamadryas baboon and Japanese monkey. Southern blot analysis showed the TSPY gene to be male specific in the primates used and disclosed variability of restriction pattern in gibbons. Fluorescence in situ hybridization demonstrated that the probe ppTSPY2372, biotinylated using polymerase chain reaction, is located as a slight signal in the proximal long arm of the Y chromosome of the white-handed gibbon, hamadryas baboon and Japanese monkey and in the middle long arm of the Y chromosome of the siamang, while a faint signal and an intense signal were detected in the proximal long arm of the Y chromosome of the aglle gibbon. These findings allow us to speculate that the gibbons might have evolved some structural differentiation in the TSPY gene. The first introns of the TSPY genes were sequenced and compared. One hundred thirty-seven of 606 sites were found to be variable, and 10 deletions/insertions were noted among these gibbons, two species of Old World monkeys and human. Sequence similarity ranged from 81.7% between humans and hamadryas baboons to 98.7% between Japanese monkeys and hamadryas baboons. These sequences may be of great use in future studies for resolving the phylogeny of gibbons and Old World monkeys.

Animals↗
PubMed1995

Molecular features and mitochondrial import pathway of the 14-kilodalton subunit of cytochrome c reductase from potato.

The cytochrome c reductase complexes from fungi and mammals both contain a 14-kD protein (yeast, 14.4 kD; bovine, 13.4 kD) that does not directly participate in electron transfer but possibly is indirectly involved in the function of the complex and has a role in assembly of the multimeric enzyme. A subunit of comparable size was identified for the bc1 complex of higher plants. The 14-kD protein from potato (Solanum tuberosum) was specifically separated from the isolated protein complex in the presence of 6 M urea and is, therefore, assumed to be a peripheral component. Direct sequence analysis of the proteins from potato and wheat (Triticum aestivum) and isolation of corresponding cDNA clones for the subunit from potato revealed clear similarity to the equivalent proteins from yeast and bovine. The wheat 14-kD protein seems to occur in two isoforms. The 14-kD protein from plants is very hydrophilic, has a characteristic charge distribution, and contains no potential membrane-spanning helices. In vitro import of the radiolabeled 14-kD protein from potato into isolated mitochondria depends on the membrane potential across the inner mitochondrial membrane. The protein seems to lack a cleavable mitochondrial presequence, because it is not processed upon translocation. Possible intramolecular regions involved in targeting of the 14-kD protein to plant mitochondria are discussed.

Amino Acid Sequence↗
PubMed1995

Molecular features of the CAG repeats and clinical manifestation of Machado-Joseph disease.

Machado--Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration mapped to chromosome 14q32.1. The CAG expansions of the MJD1 gene was identified as the cause of the disease. We have analyzed 90 MJD individuals from 62 independent MJD families and found that the MJD1 repeat length is inversely correlated with the age of onset (r = -0.87). The MJD chromosomes contained 61-84 repeat units, whereas normal chromosomes displayed 14-34 repeats. In the normal chromosomes, 14 repeat units were the most common and the shortest. In association with the clinical anticipation of the disease, a parent--child analysis showed the unidirectional expansion of CAG repeats and no case of diminution in the affected family. The differences in CAG repeat length between parent and child and between siblings are greater in paternal transmission than in maternal transmission. Detailed analysis revealed that a large degree of expansion was associated with a shorter length of MJD1 gene in paternal transmission. On the other hand, the increments of increase were similar for shorter and longer expansion in maternal transmission. Among the three clinical subtypes, type I of MJD, with dystonia, showed a larger degree of expansion in CAG repeats of the gene and younger ages of onset than the other types.

Adult↗
PubMed1999

Molecular features underlying the sequential phosphorylation of HS1 protein and its association with c-Fgr protein-tyrosine kinase.

The hematopoietic lineage cell-specific protein HS1 was shown to undergo a process of sequential phosphorylation both in vitro and in vivo, which is synergistically mediated by Syk and Src family protein-tyrosine kinases and essential for B cell antigen receptor-mediated apoptosis. We have now identified tyrosine 222 as the HS1 residue phosphorylated by the Src family protein kinases c-Fgr and Lyn, and we show that a truncated form of HS1 (HS1-208-401) lacking the N-terminal putative DNA binding region and the C-terminal Src homology 3 (SH3) domain is still able to undergo all the steps of sequential phosphorylation as efficiently as full-length HS1. We also show that a stable association of phospho-HS1 with c-Fgr through its SH2 domain requires previous autophosphorylation of the kinase and is prevented by subsequent phosphorylation of Tyr-222. Kinetic studies with HS1 and its truncated forms previously phosphorylated by Syk and with a peptide substrate reproducing the sequence around tyrosine 222 support the view that efficient phosphorylation of HS1 by Src family protein kinases entirely relies on TyrP-SH2 domain interaction with negligible, if any, contribution of local specificity determinants. Our data indicate that the proline-rich region of HS1 bordered by tyrosyl residues affected by Syk and Src family kinases represents a functional domain designed to undergo a process of sequential phosphorylation.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Identification of CD36 molecular features required for its in vitro angiostatic activity.

Thrombospondin-1 (TSP-1), a natural inhibitor of angiogenesis, acts directly on endothelial cells (EC) via CD36 to inhibit their migration and morphogenesis induced by basic fibroblast growth factor. Here we show that CD36 triggered by TSP-1 inhibits in vitro angiogenesis stimulated by vascular endothelial growth factor-A (VEGF-A). To demonstrate that the TSP-1 inhibitory signal was mediated by CD36, we transduced CD36 in CD36-deficient endothelial cells. Both TSP-1 and the agonist anti-CD36 mAb SMO, which mimics TSP-1 activity, reduced the VEGF-A165-induced migration and sprouting of CD36-ECs. To address the mechanisms by which CD36 may exert its angiostatic function, we investigated the functional components of the C-terminal cytoplasmic tail by site-directed mutagenesis. Our results indicate that C464, R467, and K469 of CD36 are required for the inhibitory activity of TSP-1. In contrast, point mutation of C466 did not alter TSP-1 ability to inhibit EC migration and sprouting. Moreover, we show that activation of CD36 by TSP-1 down-modulates the VEGF receptor-2 (VEGFR-2) and p38 mitogen-associated protein kinase phosphorylation induced by VEGF-A165, and this effect was specifically abolished by point mutation at C464. These results identify specific amino acids of the C-terminal cytoplasmic tail of CD36 crucial for the in vitro angiostatic activity of TSP-1 and extend our knowledge of regulation of VEGFR-2-mediated biological activities on ECs.

Amino Acid Sequence↗
PubMed1991

Molecular features necessary for the uptake of diamines and related compounds by the polyamine receptor of rat lung slices.

The influence of 17 putrescine analogues on the uptake of putrescine and/or paraquat by rat lung slices has been determined. Most of these compounds are competitive inhibitors of putrescine and/or paraquat uptake, but three show no inhibiting activity. Apparent Ki values of the putrescine derivatives increase, and thus the inhibitory effects decrease, with increasing N-methylation. Comparison of N-methyl-1,4-diaminobutane (Ki = 8 microM) with N,N'-bis-methyl-1,4-diaminobutane (Ki = 25.5 microM) shows that a single primary amino group is desirable for high inhibiting activity. Dimethylation at one amino function does not greatly decrease inhibitory potential (thus N,N-dimethyl-1,4-diaminobutane has Ki = 11.5 microM). Increasing the size of N-alkyl substituents in putrescine derivatives, decreased their inhibitory action on the uptake of putrescine. Investigation of the effect of conformationally-restricted analogues of putrescine shows that both (E) and (Z) isomers of 1,4-diaminobut-2-ene are poor inhibitors of putrescine uptake. Analogues of putrescine with bulky substituents on the butyl chain, i.e. the meso- and rac-isomers of 1,1-dichloro-2,3-diaminomethylcyclopropane, do not inhibit putrescine uptake. Inhibiting putrescine derivatives which contain aziridine groups are competitive inhibitors of putrescine and paraquat uptake. Surprisingly, N-(4-aminobutyl)aziridine is the most effective inhibitor of putrescine uptake studied, and is a better inhibitor of paraquat uptake than the endogenous polyamine, putrescine. N-(4-Aminobutyl)aziridine binds reversibly to the polyamine transporter and its inhibitory effects do not appear to be due to any cytotoxic activity of the aziridine. The parameter A (mM)-1 defined as 1000/Ki (where Ki units are microM) was taken as a measure of the affinity of a compound for the polyamine receptor in this paper.

Affinity Labels↗
PubMed2004

Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature.

BACKGROUND: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an uncommon type of skin lymphoma. The natural history, optimal treatment strategy, and prognostic factors associated with this malignancy are not well defined. METHODS: The authors performed a systematic analysis of all patients with SPTCL reported on in the English-language medical literature, with emphasis on specific clinical features, experiences involving the use of radiotherapy and systemic agents, and prognostic factors predictive of treatment response and clinical outcome. RESULTS: One hundred fifty-six patients with SPTCL were identified in the literature. Hemophagocytic syndrome (HPS) was a presenting feature in 37% of patients, and > 90% of patients required treatment at diagnosis. Prednisone was used frequently as initial therapy in patients who had less aggressive disease at presentation; however, durable complete remissions (CR) were infrequent. Anthracycline-based chemotherapy regimens were the most commonly used and most effective systemic treatment options, producing long-term CR in approximately 30% of patients. Among patients who received high-dose chemotherapy and stem cell transplantation (HDT-SCT) for refractory or recurrent disease, 92% achieved CR, with a median response duration of > or = 14 months. The presence of HPS at diagnosis and expression of the gamma/delta T-cell receptor (TCR) by tumor cells were associated with poor survival, whereas age was not. After a median follow-up of 24 months, 48% of patients died of disease. The median survival duration was 27 months. CONCLUSIONS: SPTCL has an aggressive natural history. Nonetheless, a subgroup of patients with SPTCL can have long-term disease remission following anthracycline-based initial therapy or subsequent HDT-SCT. HPS and the TCR phenotype may be useful prognostic markers for patients with this malignancy.

Adolescent↗
PubMed1997

Molecular features of the hepatitis B virus nucleocapsid T-cell epitope 18-27: interaction with HLA and T-cell receptor.

The strength of the cytotoxic T lymphocyte (CTL) response is believed to influence the final outcome of hepatitis B virus (HBV) infection. Among the different CTL epitopes so far identified, the sequence 18-27 of the HBV nucleocapsid antigen is widely recognized by CTL of HLA-A2-positive patients with acute self-limited HBV infection, and represents the main component of a peptide-based therapeutic vaccine aimed at stimulating the antiviral CTL response in patients with chronic hepatitis B. In the present study, we further analyzed the features of this important HBV region by the following: 1) defining the contribution of individual residues of the epitope to the interaction with the T-cell receptor (TCR) and with the HLA-A0201 molecule; 2) assessing the antigenicity of this viral region in the context of the different HLA-A2 subtypes; and 3) testing whether this sequence can stimulate not only HLA-class I but also HLA class II restricted T-cell responses. A clear hierarchy was observed in the ability of individual residues to act as TCR or HLA binding sites. Furthermore, the sequence HBc18-27 was able to be recognized by specific CTL when presented in the context of different HLA-A2 subtypes. Finally, this HBV region was also found to stimulate HLA class II restricted T-cell responses. These data further increase the potential coverage and efficacy of therapeutic vaccines based on the HBc18-27 sequence.

Adult↗