When rhinoceros species that are browsers in the wild are fed in captivity they become iron overloaded. Presumably, their iron-absorptive mechanisms have evolved to become highly efficient. In humans, mutations of the HFE gene cause increased iron absorption. To determine whether the HFE gene of rhinoceroses has undergone mutation as an adaptive mechanism to improve iron absorption from iron-poor diets, we have sequenced the entire coding region of the HFE genes of four species of rhinoceros. Two of these were browsing species and two were grazing species. Although the HFE gene has been well preserved across species, numerous nucleotide differences were found between rhinoceros and human or mouse, some of which changed deduced amino acids. Of these mutations, only one found in the black rhinoceros appears to be a viable candidate mutation that might adversely affect HFE function. This mutation, S88T, is in a highly conserved region that is involved in the interaction between transferrin receptor and HFE.

Adaptation, Physiological↗

PubMedDate not supplied

Place cell rigidity correlates with impaired spatial learning in aged rats.

In humans and in animals, some aged individuals are severely impaired in learning and memory capacity whereas others perform as well as young adults. In the present study, the spatial memory capacity of young and aged rats was characterized by the Morris water maze task, and then firing patterns of hippocampal "place cells" were assessed as the animals explored a familiar environment and a geometrically-altered version of the environment. Spatial representations of hippocampal cells in young and memory-intact aged rats changed upon exposure to the altered environment. In contrast, spatial representations of many cells in aged, memory-impaired rats were unaffected by the environmental alteration. Furthermore, combining all groups, the extent to which spatial representations distinguished the familiar and altered environments predicted learning capacity in the water maze. These findings suggest that a major component of memory impairment in aging may be the failure of the hippocampus to encode subtle differences in contextual information that differ across multiple experiences, such as the sequence of training trials in the water maze.

Aging↗

PubMedDate not supplied

Single amino acid substitutions in influenza haemagglutinin change receptor binding specificity.

The haemagglutinin (HA) glycoproteins of influenza virus membranes are responsible for binding viruses to cells by interacting with membrane receptor molecules which contain sialic acid (for review see ref. 1). This interaction is known to vary in detailed specificity for different influenza viruses (see, for example, refs 2-4) and we have attempted to identify the sialic acid binding site of the haemagglutinin by comparing the amino acid sequences of haemagglutinins with different binding specificities. We present here evidence that haemagglutinins which differ in recognizing either NeuAc alpha 2 leads to 3Gal- or NeuAc alpha 2 leads to 6Gal- linkages in glycoproteins also differ at amino acid 226 of HA1. This residue is located in a pocket on the distal tip of the molecule, an area previously proposed from considerations of the three-dimensional structure of the haemagglutinin to be involved in receptor binding.

Amino Acid Sequence↗

PubMedDate not supplied

The immunodominant site of a synthetic immunogen has a conformational preference in water for a type-II reverse turn.

Many short synthetic peptides have now been shown to induce antibodies reactive with their cognate sequences in the intact folded protein. Aside from the usefulness of such antibodies as site-specific reagents, the frequency with which this recognition occurs has raised several theoretical issues, the central one being that of how an antibody to a short synthetic peptide, which represents one of the most disordered states of a site in a protein, can react with the more ordered version of the same sequence in the folded protein. This apparent paradox can be resolved if the target site on the protein approaches disorder or if the peptide in solution or on a carrier adopts, with significant frequency, a conformation compatible with that of the cognate site in the protein. Various studies already suggest that antigenic sites in proteins correspond to regions of high atomic mobility. We now show, using high-field nuclear magnetic resonance (NMR) spectroscopy, that a nonapeptide selected by several monoclonal antibodies as the immunodominant site of a 36-amino-acid immunogen (residues 75-110 of influenza virus haemagglutinin) adopts a highly populated type-II reverse-turn conformation in water. This suggests that in this case the antibodies have selected a sequence possessing a conformational preference. Apart from helping us to understand immunological recognition, anti-peptide antibodies may provide reagents of sufficient precision for an immunological approach to the problem of protein folding.

Hydrogen Bonding↗

PubMedDate not supplied

Monoclonal antibodies against an identical short peptide sequence shared by two unrelated proteins.

Antipeptide antibodies provide the opportunity to explore the molecular basis for antigen-antibody recognition and to test theories of immune recognition. We investigated the possibility of raising monoclonal antipeptide antibodies against a specific epitope consisting of six amino acid residues, which is common to two unrelated proteins. The goal of this investigation was to analyze the reactivity of these epitope specific antibodies towards the same sequence in these two different proteins. A correlation between antibody reactivity and secondary structures of the same peptide sequence in different proteins could help to understand the ability of antipeptide antibodies to react with their cognate sequence in intact folded proteins. Monoclonal antibodies were raised against one hexamer sequence, PGTAPK, that is present in both thioredoxin and Fab New lambda-light chain. The antipeptide antibodies reacted only with thioredoxin but not with Fab New in ELISA's, immune precipitation and Western blots. Determination of the antibody specificity through binding tests with peptide analogs revealed the influence of the residue N-terminal from the hexamer epitope on antibody binding. Because of the observed influence of the N-1 adjacent residue in peptide analogs, the discrimination between the protein antigens could not be interpreted clearly as the result of the different hexamer conformations present in the native structures of the two proteins. However, analysis of the antibody reactivity with peptide analogs with varying "frame residues" surrounding the hexamer epitope indicates the possible discrimination of different peptide conformations by the antibody.

Amino Acid Sequence↗

PubMedDate not supplied

Immune recognition of viral antigens.

The response exhibited by the immune system to viral and other foreign antigens consists of antibody-mediated and T cell-mediated immunity. Structural and molecular biological studies have shown that the antibody response is tailored to provide exquisite specificity by generating binding pockets that are complementary in shape as well as in charge to the antigen. On the other hand, the cellular response uses T-cell receptors (TCRs) and the major histocompatibility complex (MHC) antigens. Structural information on the TCRs is not yet available, but the crystal structures of several MHC class I molecules have shown how one MHC molecule can bind many different peptide sequences that share only the common anchor residue positions that determine allele specificity. MHC class I interactions with the peptide backbone at the N and C termini explain the high specificity of the binding groove for peptide ligands and suggest a universal mode of recognition for peptides to MHC class I molecules. Peptide-MHC class II interactions are less well understood, although recent structural work has shown important differences in the binding clefts of MHC class I and II that lead to longer peptides being bound to class II molecules. Detailed analysis at the molecular level has indicated that conformational changes in both antibodies and MHC molecules occur upon antigen binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗