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At least 55 records · Page 3Linked to original sources
PubMed2004

Genomic organization of the mouse Msh4 gene producing bicistronic, chimeric and antisense mRNA.

By degenerate PCR and screening of mouse testis cDNA library, we have identified seven cDNAs from the meiotic recombination gene Msh4. Variant alpha and probably beta are likely involved in meiotic DNA recombination. Other variants have distinctive structures; variant epsilon, theta; and iota form a bicistronic operon, while variant delta contains antisense RNA for the endoplasmic reticulum (ER) chaperon Hspa5 gene and small open reading frame (ORF) identical to epsilon ORF2. Analysis of the exon-intron structures revealed unusual genomic organizations: the first three exons of delta and the first exon of epsilon are respectively mapped to the Hspa5 locus on chromosome 2 and the Pcbp3 locus on chromosome 10; the remaining exons of both variants are mapped to the Msh4 locus on chromosome 3. The first exon of variant beta is located on chromosome 16, while the others are located on chromosome 3. Synthesis of these mRNAs is assumed to require interchromosomal trans-splicing alone (beta and epsilon) or in combination with converse-splicing (delta). Most Msh4 variant mRNAs are mainly expressed in testis, but a small amount of each variant except for epsilon is also expressed in brain, heart, thymus, ovary and embryonic head. Enhanced green fluorescent protein (EGFP) fusion experiments showed that all the ORFs are translated, and most of those proteins are localized to a particular subcellular compartment. It also appeared that expression of variant delta induces cell death. This study suggests that the dynamic interchromosomal (intergenic) trans-splicing generates functional diversity of the mouse Msh4 gene.

Alternative Splicing↗
PubMed2002

Ligands for murine NKG2D display heterogeneous binding behavior.

NKG2D transmits stimulatory signals to natural killer cells and other hematopoietic cells, leading to enhanced proliferation, cytokine secretion and target killing. Murine and human NKG2D each recognize five known class I-related molecules with distinct primary structures. Here, we used surface plasmon resonance to examine the binding of murine NKG2D to its cognate ligands: RAE-1B6 (a newly described C57BL/6J variant of RAE-1), RAE-1 delta (common to BALB and C57BL6/J), and H60 (expressed in BALB, but not C57BL/6J). While RAE-1B6 and H60 display relatively high affinities for NKG2D with K(D) in the 20-30 nM range and k(off )in the 0.03s(-1) to 0.06s(-1) range (t(1/2) approximately 10-20s); the RAE-1 delta variant binds with a lower affinity: K(D) of approximately 750 nM. Furthermore, RAE-1 delta displays biphasic kinetics with dominant k(off) of approximately 0.2s(-1) (t(1/2) approximately 3s), partially explaining the lower affinity. Thus, H60 and RAE-1B6 bind NKG2D with almost identical kinetics while sharing only 20% amino acid sequence identity; whereas other RAE-1 molecules demonstrate faster dissociation and lower affinities than RAE-1B6 despite sharing 90% sequence identity. C57BL/6J mice, although not expressing the H60 gene product, retain a high-affinity ligand for NKG2D in the form of RAE-1B6.

Amino Acid Sequence↗
PubMed2002

CD3 delta establishes a functional link between the T cell receptor and CD8.

T cells expressing T cell receptor (TCR) complexes that lack CD3 delta, either due to deletion of the CD3 delta gene, or by replacement of the connecting peptide of the TCR alpha chain, exhibit severely impaired positive selection and TCR-mediated activation of CD8 single-positive T cells. Because the same defects have been observed in mice expressing no CD8 beta or tailless CD8 beta, we examined whether CD3 delta serves to couple TCR.CD3 with CD8. To this end we used T cell hybridomas and transgenic mice expressing the T1 TCR, which recognizes a photoreactive derivative of the PbCS 252-260 peptide in the context of H-2K(d). We report that, in thymocytes and hybridomas expressing the T1 TCR.CD3 complex, CD8 alpha beta associates with the TCR. This association was not observed on T1 hybridomas expressing only CD8 alpha alpha or a CD3 delta(-) variant of the T1 TCR. CD3 delta was selectively co-immunoprecipitated with anti-CD8 antibodies, indicating an avid association of CD8 with CD3 delta. Because CD8 alpha beta is a raft constituent, due to this association a fraction of TCR.CD3 is raft-associated. Cross-linking of these TCR-CD8 adducts results in extensive TCR aggregate formation and intracellular calcium mobilization. Thus, CD3 delta couples TCR.CD3 with raft-associated CD8, which is required for effective activation and positive selection of CD8(+) T cells.

Affinity Labels↗
PubMed2006

Laminin activates CaMK-II to stabilize nascent embryonic axons.

In neurons, the interaction of laminin with its receptor, beta1 integrin, is accompanied by an increase in cytosolic Ca2+. Neuronal behavior is influenced by CaMK-II, the type II Ca2+/calmodulin-dependent protein kinase, which is enriched in axons of mouse embryonic neurons. In this study, we sought to determine whether CaMK-II is activated by laminin, and if so, how CaMK-II influences axonal growth and stability. Axons grew up to 200 microm within 1 day of plating P19 embryoid bodies on laminin-1 (EHS laminin). Activated CaMK-II was found enriched along the axon and in the growth cone as detected using a phospho-Thr(287) specific CaMK-II antibody. beta1 integrin was found in a similar pattern along the axon and in the growth cone. Direct inhibition of CaMK-II in 1-day-old neurons immediately froze growth cone dynamics, disorganized F-actin and ultimately led to axon retraction. Collapsed axonal remnants exhibited diminished phospho-CaMK-II levels. Treatment of 1-day neurons with a beta1 integrin-blocking antibody (CD29) also reduced axon length and phospho-CaMK-II levels and, like CaMK-II inhibitors, decreased CaMK-II activation. Among several CaMK-II variants detected in these cultures, the 52-kDa delta variant preferentially associated with actin and beta 3 tubulin as determined by reciprocal immunoprecipitation. Our findings indicate that persistent activation of delta CaMK-II by laminin stabilizes nascent embryonic axons through its influence on the actin cytoskeleton.

Actin Cytoskeleton↗
PubMed2006

Structure-function analysis of delta trafficking, receptor binding and signaling in Drosophila.

The transmembrane proteins Delta and Notch act as ligand and receptor in a conserved signaling pathway required for a variety of cell fate specification events in many organisms. Binding of Delta to Notch results in a proteolytic cascade that releases the Notch intracellular domain, allowing it to participate in transcriptional activation in the nucleus. Recent research has implicated the endocytic and ubiquitylation machinery as essential components of Delta-Notch signaling. Our analysis of chimeric and missense Delta variants has delineated a number of structural requirements for Delta trafficking, receptor binding, and signaling. We find that while the Delta N-terminal domain is necessary and sufficient for binding to Notch, the integrity of the epidermal-growth-factor-like repeat (ELR) 2 is also required for Notch binding. Screening of 117 Delta mutant lines for proteins that exhibit aberrant subcellular trafficking has led to the identification of 18 Delta alleles (DlTD alleles) that encode "trafficking-defective" Delta proteins. We find, unexpectedly, that many DlTD alleles contain missense mutations in ELRs within the Delta extracellular domain. Finally, we find that two DlTD alleles contain lysine missense mutations within the Delta intracellular domain (DeltaICD) that may identify residues important for DeltaICD mono-ubiquitylation and subsequent Delta endocytosis and signaling.

Amino Acid Sequence↗
PubMed2000

The 'KMSKS' motif in tyrosyl-tRNA synthetase participates in the initial binding of tRNA(Tyr).

Variants at each position of the 'KMSKS' signature motif in tyrosyl-tRNA synthetase have been analyzed to test the hypothesis that this motif is involved in catalysis of the second step of the aminoacylation reaction (i.e., the transfer of tyrosine from the enzyme-bound tyrosyl-adenylate intermediate to the tRNA(Tyr) substrate). Pre-steady-state kinetic studies show that while the rate constants for tyrosine transfer (k(4)) are similar to the wild-type value for all of the mobile loop variants, the K230A and K233A variants have increased dissociation constants (K(d)(tRNA)( )()= 2.4 and 1.7 microM, respectively) relative to the wild-type enzyme (K(d)(tRNA)( )()= 0.39 microM). In contrast, the K(d)(tRNA) values for the F231L, G232A, and T234A variants are similar to that of the wild-type enzyme. The K(d)(tRNA) value for a loop deletion variant, Delta(227-234), is similar to that for the K230A/K233A double mutant variant (3.4 and 3.0 microM, respectively). Double mutant free energy cycle analysis indicates there is a synergistic interaction between the side chains of K230 and K233 during the initial binding of tRNA(Tyr) (DeltaDeltaG(int) = -0.74 kcal/mol). These results suggest that while the 'KMSKS' motif is important for the initial binding of tRNA(Tyr) to tyrosyl-tRNA synthetase, it does not play a catalytic role in the second step of the reaction. These studies provide the first kinetic evidence that the 'KMSKS' motif plays a role in the initial binding of tRNA(Tyr) to tyrosyl-tRNA synthetase.

Amino Acid Sequence↗
PubMed2005

Expression of estrogen receptor alpha exon-deleted mRNA variants in the human and non-human primate frontal cortex.

Although estrogen receptor alpha (ERalpha) mRNA has been detected in the primate frontal cortex, the types of ERalpha transcripts expressed, including exon-deleted variants (Delta), have not been determined in the monkey or human frontal cortex. Because the types of ERalpha mRNA expressed in brain could define neuronal responses to estrogens, we examined the transcript pool of ERalpha mRNAs expressed in normal adult and developing human and macaque frontal cortex. We reverse transcribed total RNA from the postmortem frontal cortex of 29 normal adult humans, 12 rhesus macaques, and 19 people ranging from infants to adults and employed two rounds of nested polymerase chain reaction (PCR) to generate ERalpha products spanning the coding domain. In a third nested PCR, we used primers specific for novel sequences of exon-exon junctions created when whole exons are missing. By sequencing PCR products, we detected 60 instances of 12 distinct DeltaERalpha mRNAs in adult humans and 94 instances of 13 distinct DeltaERalpha mRNAs in monkeys in differing patterns from one individual to another. In adult humans, 83% of individuals expressed at least 1 DeltaERalpha mRNA variant, and 100% of the monkeys expressed at least 1 DeltaERalpha mRNA variant. The single Delta2, Delta5, and Delta7 variants were frequently expressed in both human and monkey frontal cortex, Delta3 variants were rare in both species, and Delta6 variants were more frequently expressed in monkeys. In both species, we detected double, triple and quadruple Deltas, but these were less common than single Deltas. The pattern of human variant expression did not appear to change dramatically as a function of age. These findings imply the potential to produce different ERalpha proteins in frontal cortex, possibly with altered structure and function which may have physiological relevance for gene transcription by virtue of altered functional interactions with each other, other steroid hormone receptors, and genomic DNA.

Adolescent↗
PubMed2025

Proteomics and Phosphoproteomics Characteristics of the Rhesus Macaque Lung Infected With Original SARS-CoV-2, Delta, and Omicron Variants.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains mutate rapidly, making it crucial to study their molecular mechanisms for swift vaccine and drug development. Here, we utilized host lung proteomic and phosphoproteomic profiling to investigate the underlying pathology caused by the variants. Lung tissues infected with wild-type GD108, Delta, or Omicron BA.1 variants showed overexpression of proteins and phosphoproteins linked to the innate immune pathway, particularly in the Omicron group, with high activation of NOD-receptor and RIG-I like receptor signaling pathways. Protein-protein interaction (PPI) analysis revealed six key proteins, including antiviral innate immune response receptor RIG-I (DDX58), and five interferon-related proteins (IFIT2, ISG15, MX1, STAT1, and EIF2AK2), highlighting the importance of the innate immune response in combating all three variants. Kinase prediction analysis suggested that six kinases (DAPK1, DAPK2, DAPK3, PRACK, TTK, and MAP2K2), potentially inhibited by Fostamatinib, were activated across all three variants, and might be potential drug targets, pending further verification. Omicron infection, compared to other mutants, significantly disrupted proteins related to pulmonary structural support, like integrin and collagens, and inhibited efferocytosis, reducing the host's ability to eliminate the pathogen. These findings suggest that innate immune activation and structural disruption may contribute to Omicron-related pathology, potentially being useful for research into the molecular mechanisms underlying lung injury from SARS-CoV-2 variants.

Animals↗
PubMed2006

Delta subunit susceptibility variants E177A and R220H associated with complex epilepsy alter channel gating and surface expression of alpha4beta2delta GABAA receptors.

Most human idiopathic generalized epilepsies (IGEs) are polygenic, but virtually nothing is known of the molecular basis for any of the complex epilepsies. Recently, two GABAA receptor delta subunit variants (E177A, R220H) were proposed as susceptibility alleles for generalized epilepsy with febrile seizures plus and juvenile myoclonic epilepsy. In human embryonic kidney 293T cells, recombinant halpha1beta2delta(E177A) and halpha1beta2delta(R220H) receptor currents were reduced, but the basis for the current reduction was not determined. We examined the mechanistic basis for the current reduction produced by these variants using the halpha4beta2delta receptor, an isoform more physiologically relevant and linked to epileptogenesis, by characterizing the effects of these variants on receptor cell surface expression and single-channel gating properties. Expression of variant alpha4beta2delta(R220H) receptors resulted in a decrease in surface receptor proteins, and a smaller, but significant, reduction was observed for variant alpha4beta2delta(E177A) receptors. For both variants, no significant alterations of surface expression were observed for mixed population of wild-type and variant receptors. The mean open durations of alpha4beta2delta(E177A) and alpha4beta2delta(R220H) receptor single-channel currents were both significantly decreased compared to wild-type receptors. These data suggest that both delta(E177A) and delta(R220H) variants may result in disinhibition in IGEs by similar cellular and molecular mechanisms, and in heterozygously affected individuals, a reduction in channel open duration of delta subunit-containing GABAA receptors may be the major contributor to the epilepsy phenotypes.

Amino Acid Substitution↗
PubMed2004

Scattered Hammond plots reveal second level of site-specific information in protein folding: phi' (beta++).

Site-specific information about structural heterogeneities of the protein-folding transition-state ensemble is commonly derived from the scatter of the Brønsted plot through the individual values of = Delta logk(f)/Delta logK(D-N). Here, we provide a second level of site-specific detail in the transition-state analysis by demonstrating that the scatter of the Hammond plot is related to heterogeneities in the -value growth. That is, the extent of transition-state movement (Delta beta(++)) is proportional to the free-energy gradient of the mutational perturbation across the top of the activation barrier, '(beta(++)) proportional, variant Delta logK(D-N). The analysis is applied to the two-state protein L23 where the site-specific free-energy gradients are used to identify the interactions that show the highest degree of consolidation after crossing the barrier top. These interactions are distributed as a shell around the high- initiation point and denote the side-chain contacts that add criticality to the folding nucleus.

Data Interpretation, Statistical↗
PubMed1998

Two new p73 splice variants, gamma and delta, with different transcriptional activity.

p73 has been recently identified as a new structural and functional homologue of the transcription factor p53. It is expressed in either a full-length form, alpha, or a shorter beta mRNA variant, with exon 13 spliced out. Here we report the identification and functional characterization of two new p73 splicing variants, gamma (splicing out exon 11) and delta (splicing out exons 11, 12, and 13). Both gamma and delta p73 variants are expressed in human peripheral blood lymphocytes, primary keratinocytes, and different tumor cell lines, including neuroblastoma, glioblastoma, melanoma, hepatoma, and leukemia. The expression pattern of the four p73 splicing variants differs in both primary cells of different lineage and established cell lines even within the same type of tumor. A two-hybrid assay was used to characterize the homodimeric and heterodimeric interactions between the p73 variants, and showed that neither p73gamma nor p73delta interact with p53, whereas p73gamma showed strong interactions with all p73 isoforms, and p73delta binds efficiently p73alpha and p73gamma but only weakly p73beta. At the functional level, p73gamma is significantly less efficient in activating transcription of the p21(Waf1/Cip1) promoter than p53 or p73beta, whereas the effect of p73delta is intermediate and comparable to that of p73alpha. The ability of the different p73 variants to affect cell growth in p53 null osteosarcoma SAOS-2 cells correlates with their transcriptional activity on the p21(Waf1/Cip1) promoter: p73beta is the most efficient in inhibiting colony formation, whereas p73gamma is almost ineffective. Our results suggest that p73 isoforms may be differentially regulated, with four different isoforms capable of interacting among themselves and with p53. The relative expression level of each splice variant may modulate p73 transcriptional and growth suppression activities by affecting heterodimer formation.

Alternative Splicing↗