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D Mahadevan

Publications and source records attributed to D Mahadevan.

8 recordsLinked to original sources
PubMed1991

Structure of oligomeric beta B2-crystallin: an application of the T2 translation function to an asymmetric unit containing two dimers.

The molecular structure of the main subunit of the beta-crystallins, components of the vertebrate eye lens, has recently been solved by molecular replacement at 2.1 A resolution [Bax, Lapatto, Nalini, Driessen, Lindley, Mahadevan, Blundell & Slingsby (1990). Nature (London), 347, 776-780]. The protein, beta B2, is a dimer in solution, but a tetramer in the crystal with one subunit in the asymmetric unit of space group I222. Using the crystallographic dimer from this I-centred form the structure of a C222 crystal form of the beta B2 protein with four subunits in the asymmetric unit has now been solved by molecular replacement at 3.3 A. The solution involved the use of a new translation function for non-crystallographic symmetry, based on the T2 function of Crowther & Blow [Acta Cryst. (1967), 23, 544-548].

Crystallins↗
PubMed1991

Molecular model-building of amylin and alpha-calcitonin gene-related polypeptide hormones using a combination of knowledge sources.

Amylin is the major component of the amyloid found in the pancreases of noninsulin-dependent diabetics (type 2 diabetes). It is a 37 amino acid polypeptide and has been shown to have 46% sequence identity with the neuropeptide alpha-calcitonin gene-related peptide (alpha-CGRP). Both amylin and alpha-CGRP are known to be potent inhibitors of glycogen synthesis in stripped rat soleus muscle. Secondary structure prediction and tertiary structure model-building show the two polypeptides to have an alpha-helix/beta-strand motif similar to that observed in the insulin B-chain. The results have been supported by CD spectroscopy, although there is no sequence similarity between insulin and amylin/alpha-CGRP. Aggregation states have been predicted based on the dimeric and hexameric arrangements seen in porcine insulin. Rat and hamster amylin have a changed sequence motif in the beta-strand which results in lack of amyloid formation and type 2 diabetes. This, we propose, is caused by disruption of hydrogen bonding which prevents the formation of the dimer.

Algorithms↗
PubMed1990

X-ray analysis of beta B2-crystallin and evolution of oligomeric lens proteins.

The beta, gamma-crystallins form a class of homologous proteins in the eye lens. Each gamma-crystallin comprises four topologically equivalent, Greek key motifs; pairs of motifs are organized around a local dyad to give domains and two similar domains are in turn related by a further local dyad. Sequence comparisons and model building predicted that hetero-oligomeric beta-crystallins also had internally quadruplicated subunits, but with extensions at the N and C termini, indicating that beta, gamma-crystallins evolved in two duplication steps from an ancestral protein folded as a Greek key. We report here the X-ray analysis at 2.1 A resolution of beta B2-crystallin homodimer which shows that the connecting peptide is extended and the two domains separated in a way quite unlike gamma-crystallin. Domain interactions analogous to those within monomeric gamma-crystallin are intermolecular and related by a crystallographic dyad in the beta B2-crystallin dimer. This shows how oligomers can evolve by conserving an interface rather than connectivity. A further interaction between dimers suggests a model for more complex aggregates of beta-crystallin in the lens.

Amino Acid Sequence↗
PubMed1990

Prediction of domain organisation and secondary structure of thyroid peroxidase, a human autoantigen involved in destructive thyroiditis.

Organ specific autoimmune diseases are relatively common immunological disorders in man which include thyroid autoimmune disease, insulin-dependent diabetes mellitus and myasthenia gravis. The target autoantigens in some of these diseases have recently been characterised. In thyroid autoimmune disease this includes the key enzyme, thyroid peroxidase (TPO), which is involved in the generation of thyroid hormone. Structural knowledge about autoantigens such as thyroid peroxidase will allow a greater understanding of the interaction between autoantigens and the aberrant immune response, and facilitate the development of strategies for antigen-specific therapeutic manipulation. We report here a prediction of the secondary structure of thyroid peroxidase, together with the results of circular dichroic spectroscopy of a homologous purified enzyme. A combination of 3 secondary structure prediction programs has been used, following multiple sequence alignment, and TPO has been found to consist mainly of alpha-helical conformation, with little beta-sheet present. This structure prediction, together with knowledge of the exon-intron boundaries allows a model for the domain organisation of the TPO molecule to be proposed.

Amino Acid Sequence↗
PubMed1990

Protection against membrane-mediated cytotoxicity by calcium and zinc.

Injection of S. aureus alpha toxin or ultraviolet-inactivated Sendai virus into the mammary gland of lactating mice leads to cytopathic changes in the alveolar cells compatible with a breakdown of their permeability barrier. Simultaneous administration of Ca2+ or Zn2+ prevents such changes, as it does when added to alveolar cells in vitro. It is concluded that increased levels of Zn2+ (and under certain conditions of Ca2+) may exert a protective role that is clinically significant.

Animals↗
PubMed1988

Evolutionary and functional relationships between the basic and acidic beta-crystallins.

beta-Crystallins are complex oligomers composed of many related subunits. In order to understand their interactions we have built molecular models of several bovine beta-crystallins, based on their sequence similarity to the well-defined gamma-II crystallin structure, using interactive computer graphics techniques. Their common origin with gamma-crystallin is displayed in both the retention of four-fold sequence repeats of critical residues involved with stabilizing a folded beta-hairpin and the conservation of core-filling hydrophobic side-chains. The beta-crystallins have been built as bilobal molecules with each domain composed of two 'Greek key' motifs which associate about an approximate two-fold axis to form beta-sheets. The beta-crystallin sequences have previously been shown to comprise two families, the basic and acidic subunits, which have extensions of sequence. The three-dimensional models show how the two families appear to stabilize the folded beta-hairpin in the N- and C-terminal domains in ways which suggest that they have diverged from a common ancestor in different ways. Acidic beta-crystallins, like gamma-crystallins, have a regular array of charges on their N-terminal domain which has been interrupted in basic beta-crystallins by hydrophobic residues which may be related to the presence of a C-terminal extension. beta-Crystallins are more highly charged than gamma-crystallins although their charge density is higher in certain regions of the N-terminal domain, particularly in beta B1-crystallin. beta-crystallins also differ from gamma-crystallins in the virtual absence of core-filling sulphydryl groups whereas they have numerous sulphur-containing side-chains together with tryptophan and histidine rings protruding from the globular domains, particularly in the acidic subunits. The burial of these residues in subunit contacts is consistent with their spectroscopic and electrostatic properties. Protein subunit aggregation commonly occurs through hydrophobic interaction or beta-sheet extension. Analysis of the subunit surfaces has identified an N-terminal hydrophobic region common to beta B1 and beta B2 whereas a C-terminal hydrophobic loop region is common to beta B1 and beta A1 and may be correlated with their association properties. It is suggested that the polar C-terminal domain of beta B2 contributes towards the solubility of higher aggregates by interactions involving beta-sheet structure.

Amino Acid Sequence↗