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PubMed1983

H-2D products do not affect lysis of Kk target cells by Kk-specific cytotoxic T cells.

Antigens coded by the major histocompatibility complex (MHC) stimulate a large number of cytotoxic T lymphocyte (CTL) precursors. Matzinger and Bevan have suggested that the high alloreactivity is a result of the formation of interaction antigens between MHC and non-MHC-coded antigens. Previous work by Langhorne and Fischer Lindahl did not support this hypothesis. In this report we describe are improved culture system to show that the recognition of Kk target cells by Kk-specific clones is also unaffected by H-2D products. Using such a culture system, which controls for the induction of nonspecific CTL by interleukin 2 (T cell growth factor) we were also able to confirm the original conclusion of Langhorne and Fischer Lindahl that polymorphic minor histocompatibility antigens do not significantly contribute to putative "interaction antigens" formed by MHC and other antigens.

Animals↗
PubMed1999

Origins of DNA-binding specificity: role of protein contacts with the DNA backbone.

A central question in protein-DNA recognition is the origin of the specificity that permits binding to the correct site in the presence of excess, nonspecific DNA. In the P22 Arc repressor, the Phe-10 side chain is part of the hydrophobic core of the free protein but rotates out to pack against the sugar-phosphate backbone of the DNA in the repressor-operator complex. Characterization of a library of position 10 variants reveals that Phe is the only residue that results in fully active Arc. One class of mutants folds stably but binds operator with reduced affinity; another class is unstable. FV10, one member of the first class, binds operator DNA and nonoperator DNA almost equally well. The affinity differences between FV10 and wild type indicate that each Phe-10 side chain contributes 1.5-2.0 kcal to operator binding but less than 0.5 kcal/mol to nonoperator binding, demonstrating that contacts between Phe-10 and the operator DNA backbone contribute to binding specificity. This appears to be a direct contribution as the crystal structure of the FV10 dimer is similar to wild type and the Phe-10-DNA backbone interactions are the only contacts perturbed in the cocrystal structure of the FV10-operator complex.

Amino Acid Sequence↗
PubMed2003

Nucleic acid recognition by OB-fold proteins.

The OB-fold domain is a compact structural motif frequently used for nucleic acid recognition. Structural comparison of all OB-fold/nucleic acid complexes solved to date confirms the low degree of sequence similarity among members of this family while highlighting several structural sequence determinants common to most of these OB-folds. Loops connecting the secondary structural elements in the OB-fold core are extremely variable in length and in functional detail. However, certain features of ligand binding are conserved among OB-fold complexes, including the location of the binding surface, the polarity of the nucleic acid with respect to the OB-fold, and particular nucleic acid-protein interactions commonly used for recognition of single-stranded and unusually structured nucleic acids. Intriguingly, the observation of shared nucleic acid polarity may shed light on the longstanding question concerning OB-fold origins, indicating that it is unlikely that members of this family arose via convergent evolution.

Amino Acid Motifs↗
PubMed2004

Multistage classification and recognition that employs vector quantization coding and criteria extracted from nonorthogonal and preprocessed signal representations.

Classification decision tree algorithms have recently been used in pattern-recognition problems. In this paper, we propose a self-designing system that uses the classification tree algorithms and that is capable of recognizing a large number of signals. Preprocessing techniques are used to make the recognition process more effective. A combination of the original, as well as the preprocessed, signals is projected into different transform domains. Enormous sets of criteria that characterize the signals can be developed from the signal representations in these domains. At each node of the classification tree, an appropriately selected criterion is optimized with respect to desirable performance features such as complexity and noise immunity. The criterion is then employed in conjunction with a vector quantizer to divide the signals presented at a particular node in that stage into two approximately equal groups. When the process is complete, each signal is represented by a unique composite binary word index, which corresponds to the signal path through the tree, from the input to one of the terminal nodes of the tree. Experimental results verify the excellent classification accuracy of this system. High performance is maintained for both noisy and corrupt data.

Journal Article↗
PubMed1997

The initiation of simian virus 40 DNA replication in vitro.

DNA replication is a complicated process that is largely regulated during stages of initiation. The Siman Virus 40 in vitro replication system has served as an excellent model for studies of the initiation of DNA replication, and its regulation, in eukaryotes. Initiation of SV40 replication requires a single viral protein termed T-antigen, all other proteins are supplied by the host. The recent determination of the solution structure of the T-antigen domain that recognizes the SV40 origin has provided significant insights into the initiation process. For example, it has afforded a clearer understanding of origin recognition, T-antigen oligomerization, and DNA unwinding. Furthermore, the Simian virus 40 in vitro replication system has been used to study nascent DNA formation in the vicinity of the viral origin of replication. Among the conclusions drawn from these experiments is that nascent DNA synthesis does not initiate in the core origin in vitro and that Okazaki fragment formation is complex. These and related studies demonstrate that significant progress has been made in understanding the initiation of DNA synthesis at the molecular level.

Animals↗
PubMed1998

Specific amino acid recognition by aspartyl-tRNA synthetase studied by free energy simulations.

Specific amino acid binding by aminoacyl-tRNA synthetases is necessary for correct translation of the genetic code. To obtain insight into the origin of the specificity, the binding to aspartyl-tRNA synthetase (AspRS) of the negatively charged substrate aspartic acid and the neutral analogue asparagine are compared by use of molecular dynamics and free energy simulations. Simulations of the Asn-AspRS complex show that although Asn cannot bind in the same position as Asp, several possible positions exist 1.5 to 2 A away from the Asp site. The binding free energy of Asn in three of these positions was compared to that of Asp through alchemical free energy simulations, in which Asp is gradually mutated ito Asn in the complex with the enzyme. To correctly account for the electrostatic interactions in the system (including bulk solvent), a recently developed hybrid approach was used, in which the region of the mutation site is treated microscopically, whereas distant protein and solvent are treated by continuum electrostatics. Seven free energy simulations were performed in the protein and two in solution. The various Asn positions and orientations sampled at the Asn endpoints of the protein simulations yielded very similar free energy differences. The calculated Asp-->Asn free energy change is 79.8(+/-1.5) kcal/mol in solution and 95.1(+/-2.8) kcal/mol in the complex with the protein. Thus, the substrate Asp is predicted to bind much more strongly than Asn, with a binding free energy difference of 15.3 kcal/mol. This implies that erroneous binding of Asn by AspRS is highly improbable, and cannot account for any errors in the translation of the genetic code. Almost all of the protein contributions to the Asp versus Asn binding free energy difference arise from an arginine and a lysine residue that hydrogen bond to the substrate carboxylate group and an Asp and a Glu that hydrogen bond to these; all four amino acid residues are completely conserved in AspRSs. The protein effectively "solvates" the Asp side-chain more strongly than water does. The simulations are analyzed to determine the interactions that Asn is able to make in the binding pocket, and which sequence differences between AspRS and the highly homologous AsnRS are important for modifying the amino acid specificity. A double or triple mutation of AspRS that could make it specific for Asn is proposed, and supported by preliminary simulations of a mutant complex.

Amino Acid Sequence↗
PubMed1989

The evolution of MHC restrictions in antigen recognition by T cells in a haploidentical bone marrow transplant recipient.

We have longitudinally followed the major histocompatibility complex (MHC) restrictions that govern the response of T lymphocytes to specific Ag in a child with severe combined immunodeficiency who was successfully transplanted by using T cell depleted haploidentical maternal bone marrow cells and immunized shortly afterwards with tetanus toxoid (TT) Ag. In the first year post-transplant, monocytes were of both donor and recipient origin whereas T and B cells were of donor origin. Three years after transplant, all monocytes and T and B cells were of donor origin. T lymphocytes taken from the child at that time and depleted in vitro of alloreactivity to paternal Ag proliferated in response to TT presented by maternal as well as paternal monocytes. A TT-specific T cell line established from these cells in the presence of maternal monocytes cooperated with maternal but not with paternal monocytes, whereas a TT-specific T cell line established in the presence of paternal monocytes cooperated with paternal but not with maternal monocytes and with monocytes derived from a paternal uncle who shared the haplotype inherited by the recipient from her father. These results show that long-term memory T cells restricted to recipient MHC Ag not shared with the bone marrow donor continue to circulate long after the disappearance of accessory cells of recipient origin. These T cells could potentially participate in a secondary immune response because they were shown to recognize TT presented by recipient fibroblasts induced to express class II MHC molecules following treatment with IFN-gamma.

B-Lymphocytes↗
PubMed1991

Replication factors required for SV40 DNA replication in vitro. I. DNA structure-specific recognition of a primer-template junction by eukaryotic DNA polymerases and their accessory proteins.

Eukaryotic DNA polymerase delta and its accessory proteins are essential for SV40 DNA replication in vitro. A multi-subunit protein complex, replication factor C (RF-C), which is composed of subunits with apparent molecular weights of 140,000, 41,000, and 37,000, has primer/template binding and DNA-dependent ATPase activities. UV-cross-linking experiments demonstrated that the Mr = 140,000 subunit recognizes and binds to the primer-template DNA, whereas the Mr = 41,000 polypeptide binds ATP. Assembly of a replication complex at a primer-template junction has been studied in detail with synthetic, hairpin DNAs. Following glutaraldehyde fixation, a gel shift assay demonstrated that RF-C alone forms a weak binding complex with the hairpin DNA. Addition of ATP or its nonhydrolyzable analogue, ATP gamma S, increased specific binding to the DNA. Footprinting experiments revealed that RF-C recognizes the primer-template junction, covering 15 bases of the primer DNA from the 3'-end and 20 bases of the template DNA. Another replication factor, proliferating cell nuclear antigen (PCNA) binds to RF-C and the primer-template DNA forming a primer recognition complex and extends the protected region on the duplex DNA. This RF-C.PCNA complex has significant single-stranded DNA binding activity in addition to binding to a primer-template junction. However, addition of another replication factor, RF-A, completely blocked the nonspecific, single-stranded DNA binding by the RF-C.PCNA complex. RF-A therefore functions as a specificity factor for primer recognition. In the absence of RF-C, DNA polymerase delta (pol delta) and PCNA form a complex at the primer-template junction, protecting exactly the same site as the primer recognition complex. Addition of RF-C to this complex produced a higher order complex which is unstable unless its formation is coupled with translocation of pol delta. These results suggest that the sequential binding of RF-C, PCNA, and pol delta to a primer-template junction might directly account for the initiation of leading strand DNA synthesis at a replication origin. We demonstrate this directly in an accompanying paper (Tsurimoto, T., and Stillman, B. (1991) J. Biol. Chem. 266, 1961-1968).

Adenosine Triphosphate↗
PubMed2001

Bridged bis(beta-cyclodextrin)s possessing coordinated metal center(s) and their inclusion complexation behavior with model substrates: enhanced molecular binding ability by multiple recognition.

To investigate quantitatively the cooperative binding ability of several beta-cyclodextrin oligomers bearing single or multiligated metal center(s), the inclusion complexation behavior of four bis(beta-cyclodextrin)s (2-5) linked by 2,2'-bipyridine-4,4'-dicarboxy tethers and their copper(II) complexes (6-9) with representative dye guests, i.e., methyl orange (MO), acridine red (AR), rhodamine B (RhB), ammonium 8-anilino-1-naphthalenesulfonic acid (ANS), and sodium 6-(p-toludino)-2-naphthalenesulfonate (TNS), have been examined in aqueous solution at 25 degrees C by means of UV-vis, circular dichroism, fluorescence, and 2D NMR spectroscopy. The results obtained indicate that bis(beta-cyclodextrin)s 2-5 can associate with one or three copper(II) ion(s) producing 2:1 or 2:3 bis(beta-cyclodextrin)-copper(II) complexes. These metal-ligated oligo(beta-cyclodextrin)s can bind two model substrates to form intramolecular 2:2 host-guest inclusion complexes and thus significantly enhance the original binding abilities of parent beta-cyclodextrin and bis(beta-cyclodextrin) toward model substrates through the cooperative binding of two guest molecules by four tethered cyclodextrin moieties, as well as the additional binding effect supplied by ligated metal center(s). Host 6 showed the highest enhancement of the stability constant, up to 38.3 times for ANS as compared with parent beta-cyclodextrin. The molecular binding mode and stability constant of substrates by bridged bis- and oligo(beta-cyclodextrin)s 2-9 are discussed from the viewpoint of the size/shape-fit interaction and molecular multiple recognition between host and guest.

Algorithms↗
PubMed1997

Co-receptor-independent signal transduction in a mismatched CD8+ major histocompatibility complex class II-specific allogeneic cytotoxic T lymphocyte.

The contribution of co-receptors in signal transduction upon T cell receptor (TCR)-mediated recognition of major histocompatibility complex (MHC) class II antigen by mature T lymphocytes expressing TCR derived from the apparently co-receptor-independent, I-Ak-specific allogeneic CD8+ CTL clone QM11 has been examined. Mature double-negative, CD8+ and CD4+ bulk T cell lines and clones expressing TCR(QM11) were developed from TCR(QM11) transgenic mice. All these T cells, irrespective of co-receptor expression, showed specific lytic activity on cells expressing I-Ak. Furthermore, co-receptorless mutants were obtained from a CD4+ and CD8+ clone. The responses of these co-receptorless mutants upon specific recognition of the alloantigen, as judged by cytolytic activity, granule exocytosis, lymphokine production, proliferation, and tyrosine phosphorylation of the zeta chain, were comparable to those of the original clones. Thus, the results proved the co-receptor independence of the recognition of I-Ak by TCR(QM11) and further indicated there is no indispensable unique signal transduced by co-receptors. However, when the amount of the available antigen was limited by anti-I-Ak antibody, the CD4+ T cell clone showed a remarkable resistance to the inhibition whereas the mismatched CD8+ clone was readily inhibitable. The anti-I-Ak-resistant component of the CD4+ clone showed dependency on the CD4 molecule. Taken collectively, the results indicate that the role played by a co-receptor molecule in mature T cells is purely quantitative amplification of the signal through the formation of a TCR/MHC/co-receptor ternary complex, and also indicate that the role of co-receptor molecules as TCR-independent adhesion molecules is at best minimal.

Animals↗
PubMed2005

The molecular origins of specificity in the assembly of a multienzyme complex.

The pyruvate dehydrogenase (PDH) multienzyme complex is central to oxidative metabolism. We present the first crystal structure of a complex between pyruvate decarboxylase (E1) and the peripheral subunit binding domain (PSBD) of the dihydrolipoyl acetyltransferase (E2). The interface is dominated by a "charge zipper" of networked salt bridges. Remarkably, the PSBD uses essentially the same zipper to alternately recognize the dihydrolipoyl dehydrogenase (E3) component of the PDH assembly. The PSBD achieves this dual recognition largely through the addition of a network of interfacial water molecules unique to the E1-PSBD complex. These structural comparisons illuminate our observations that the formation of this water-rich E1-E2 interface is largely enthalpy driven, whereas that of the E3-PSBD complex (from which water is excluded) is entropy driven. Interfacial water molecules thus diversify surface complementarity and contribute to avidity, enthalpically. Additionally, the E1-PSBD structure provides insight into the organization and active site coupling within the approximately 9 MDa PDH complex.

Binding Sites↗
PubMed2006

Selective photolabeling of Lck kinase in complex proteome.

A molecular probe that selectively tags Lck, a Src-family kinase, was developed. This probe was one of many compounds originally designed to target the active site of tyrosine kinases in general. To our surprise, however, the probe almost exclusively labeled Lck even in a lysate of Jurkat cells. This finding led us to further characterize this probe-Lck complex by a series of photolabeling and mass spectrometric analyses. The probe-binding site on Lck was located within the well-conserved region of Src-family kinases, as we originally expected. However, the unexpected selectivity of this probe toward Lck suggests that subtle factors, which are difficult to predict based on static crystal structures, play important roles in probe recognition.

Amino Acid Sequence↗
PubMed1996

An Artificial Receptor for Dimethyl Aspartate.

[trans-5,15-Bis(2,7-dihydroxy-1-naphthyl)-2,3,7,8,12,13,17,18-octaethylporphyrinato]zinc(II) (1), a trifunctionalized porphyrin host, was prepared as a receptor for amino acid derivatives, particularly those having a hydrogen-bonding site in the side chain. The free energy changes for the binding of Leu-OMe, Asp-OMe, and Glu-OMe to 1 were -5.8 kcal/mol, -6.6 kcal/mol, and -5.9 kcal/mol, showing a selectivity for Asp-OMe. (1)H NMR titration experiments indicated that three simultaneous attractive interactions, one coordination interaction, and two hydrogen-bonding interactions, are operating in the host-guest complex. The preference for Asp-OMe over Glu-OMe was found to originate from the favorable enthalpy term for Asp-OMe. The free energy change, the enthalpy change, and the entropy change were determined and split into contributions arising from coordination interaction and from hydrogen-bonding interactions by use of reference hosts. Comparison of enthalpy and entropy changes suggests that the host-guest complex becomes more ordered as the number of recognition pairs increases.

Journal Article↗
PubMed2001

The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor.

We describe a novel mammalian DNA binding activity that requires at least two symmetrically methylated CpG dinucleotides in its recognition sequence, preferably within the sequence 5'CGCG. A key component of the activity is Kaiso, a protein with POZ and zinc-finger domains that is known to associate with p120 catenin. We find that Kaiso behaves as a methylation-dependent transcriptional repressor in transient transfection assays. Kaiso is a constituent of one of two methyl-CpG binding complexes originally designated as MeCP1. The data suggest that zinc-finger motifs are responsible for DNA binding, and may therefore target repression to specific methylated regions of the genome. As Kaiso associates with p120 catenin, Kaiso may link events at the cell surface with DNA methylation-dependent gene silencing.

Animals↗
PubMed2004

Recognition by symmetry derivatives and the generalized structure tensor.

We suggest a set of complex differential operators that can be used to produce and filter dense orientation (tensor) fields for feature extraction, matching, and pattern recognition. We present results on the invariance properties of these operators, that we call symmetry derivatives. These show that, in contrast to ordinary derivatives, all orders of symmetry derivatives of Gaussians yield a remarkable invariance: They are obtained by replacing the original differential polynomial with the same polynomial, but using ordinary coordinates x and y corresponding to partial derivatives. Moreover, the symmetry derivatives of Gaussians are closed under the convolution operator and they are invariant to the Fourier transform. The equivalent of the structure tensor, representing and extracting orientations of curve patterns, had previously been shown to hold in harmonic coordinates in a nearly identical manner. As a result, positions, orientations, and certainties of intricate patterns, e.g., spirals, crosses, parabolic shapes, can be modeled by use of symmetry derivatives of Gaussians with greater analytical precision as well as computational efficiency. Since Gaussians and their derivatives are utilized extensively in image processing, the revealed properties have practical consequences for local orientation based feature extraction. The usefulness of these results is demonstrated by two applications: 1) tracking cross markers in long image sequences from vehicle crash tests and 2) alignment of noisy fingerprints.

Dermatoglyphics↗
PubMed2002

Analysis of phylogenetic relationship of Cylindrocarpon lichenicola and Acremonium falciforme to the Fusarium solani species complex and a review of similarities in the spectrum of opportunistic infections caused by these fungi.

An emerging pattern of similarity in medical case reports led to a project to compare the phylogenetic affinities of two well-known tropical fungal opportunistic pathogens, Cylindrocarpon lichenicola and Acremonium falciforme, to members of the Fusarium solani species complex. C. lichenicola and A. falciforme, despite their deviating conidial morphologies, were shown via sequencing of the ribosomal large subunit to be well instituted within a clade mainly consisting of typical F. solani strains and other species until recently considered variants of F. solani. The original name Fusarium lichenicola C. B. Massalongo is reestablished, and the new combination F. falciforme is made. Recognition of these species as fusaria is necessary for correct interpretation of current and future molecular diagnostic tests. Reevaluation of species morphology in light of the molecular findings showed that certain features, especially elongate filiform conidiophores with integrated terminal phialides, facilitate correct microscopic classification of these atypical Fusarium species. There is a strong and underrecognized overlap in the spectra of cases caused by members of the F. solani clade, particularly ocular infections, mycetomas, and, in the neutropenic host, disseminated and other serious systemic infections. A novel synthesis of case reports shows that patients from areas with warm climates may develop a distinctive fusarial intertrigo caused by F. solani, Fusarium lichenicola, or Fusarium oxysporum.

Acremonium↗
PubMed1998

The activating form of CD94 receptor complex: CD94 covalently associates with the Kp39 protein that represents the product of the NKG2-C gene.

Inhibitory receptor complexes formed by CD94 and NKG2-A (Kp43) molecules have been implicated in HLA class I recognition by human natural killer (NK) cells. Additional forms of CD94 receptors have recently been described in NK cells characterized by the lack of NKG2-A expression. These CD94 receptors were shown to display activating functions. Immunoprecipitation with anti-CD94 monoclonal antibodies (mAb) led to the identification, in these cells, of a 39-kDa (Kp39) molecule that was originally believed to represent an activating isoform of the CD94 molecules. In the present study we show that the Kp39 molecule is covalently associated with CD94 and displays a protein backbone (26 kDa) similar to that of NKG2-A (Kp43) glycoproteins. Peptide mapping analysis indicates that Kp39 and NKG2-A glycoproteins belong to the same molecular family. A novel NKG2-specific mAb (termed P25) has been generated that specifically reacts with both NKG2-A and NKG2-C molecules, but fails to recognize NKG2-E molecules. Analysis of polyclonal and clonal NK cells shows that P25 mAb reacts with all NKG2-A+ cells and with a fraction of CD94+ cells lacking the expression of NKG2-A. These data indicate that NKG2-C molecules are indeed expressed only in a subset of cells lacking the expression of NKG2-A. The CD94-associated Kp39 molecule can be detected only in NKG2-A- P25+ cells, i.e. cells expressing NKG2-C molecules. Indeed, reverse transcription-polymerase chain reaction analysis performed on a large panel of NK clones indicates that NKG2-A- P25+ NK clones express the NKG2-C transcript. Notably, the cytolytic activity of these clones can be triggered by the P25 mAb in redirected killing analysis. Finally, biochemical analysis of COS7 cells cotransfected with CD94 and NKG2-C demonstrates the identity between Kp39 and NKG2-C molecules. Altogether, our data demonstrate that NKG2-C molecules associate with CD94 to form an activating receptor complex in a subset of human NK cells.

Amino Acid Sequence↗
PubMed2002

Phylogeographic analysis of a recent radiation of Enallagma damselflies (Odonata: Coenagrionidae).

A phylogenetic hypothesis revealed two recent radiations among species of Enallagma damselflies, and extensive ecological work suggests that both adaptive and nonadaptive processes are involved in these radiations. We analysed the geographical pattern of genetic variability at 868 bp of mitochondrial DNA (mtDNA) among 283 individuals of 5 species displaying little ecological differentiation to identify the ancestral lineage, support their independent evolutionary trajectories and identify historical events and the underlying mechanism for one of these radiations. Nested clade analysis results clearly support a past event of range fragmentation in E. hageni. These Atlantic and Continental hageni races experienced distinct dispersal histories and still maintain nearly nonoverlapping ranges All four other species derive from the Continental hageni. Whereas three species endemic to the Atlantic coastal plain show little genetic variation, E. ebrium shared several haplotypes with the Continental hageni. Contrasting levels of genetic differentiation between E. hageni and E. ebrium in geographical areas associated with distinct events of E. hageni's recent history support the recent origin of this species. Altogether, our results are compatible with a process of radiation via divergence in mate recognition systems within the Continental hageni race following secondary contacts between putative refugial races.

Animals↗