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PubMed1993

The primary structures and properties of non-stomach lysozymes of sheep and cow, and implication for functional divergence of lysozyme.

Lysozymes were purified from the homogenate of cow and sheep kidneys, and their amino-acid sequences as well as some enzymic properties were determined. Like most mammalian lysozymes both sheep and cow kidney lysozymes are composed of 130 amino acids. The sequences of these two lysozymes are the most similar to each other (95% identity), the second most similar to the conventional mammalian lysozymes like human, rat and rabbit lysozymes (74-85% identity), and much less similar to their own stomach lysozymes (65-70% identity). Cow kidney lysozyme is also different from cow milk lysozyme (partial sequence), indicating that cow contains at least three kinds of chicken type lysozymes, that is kidney, milk and stomach lysozymes. The activities of cow and sheep kidney lysozymes were 3% and 29% against Micrococcus luteus at pH 7.0, ionic strength of 0.1 and 30 degrees C, and 57% and 84% against glycol chitin at pH 5.5 and 40 degrees C, which were expressed as percentages relative to hen lysozyme. The net charges of cow and sheep lysozymes at pH 7 were less positive (+1.5 and +2.5, respectively) than human and hen lysozymes (both +8.0) and rather close to the stomach ones (-2 to 0). The decreased net positive charge observed in cow and sheep kidney lysozymes may suggest that the ruminant kidney lysozyme had functioned once as a digestive enzyme in the stomach of an ancestral ruminant.

Amino Acid Sequence↗
PubMed2002

Expression, localization and functional divergence of alphaB-crystallin and heat shock protein 27 in core myopathies and neurogenic atrophy.

AlphaB-crystallin (alphaBC) and heat shock protein 27 (hsp 27) are members of the family of small heat shock proteins (shsps), which exert a role as molecular chaperones by binding unfolded or denatured proteins, thereby suppressing irreversible protein aggregation and consecutive cell damage. The essential role of shsps in human neuromuscular disorders is highlighted by the observation that a mutation of the human alphaBC gene causes an autosomal dominant "myofibrillar myopathy" characterized by alphaBC and desmin accumulation. Furthermore, an aberrant immunostaining of alphaBC was recently reported in sporadic inclusion body myositis. In the present study we analyzed the expression and localization of alphaB-crystallin and hsp 27 in various congenital myopathies by means of indirect immunofluorescence, immunogold electron microscopy and Western blotting. We demonstrate an increased immunoreactivity of alphaBC and hsp 27 in central and minicore lesions as well as in target fibers, which renders both shsps as reliable, but nonspecific, markers for core and target structures. In contrast, Western blotting demonstrated a normal expression level of alphaBC and hsp 27, which indicates that the increased immunostaining is not the result of an enhanced protein expression. Furthermore, thiocyanate-induced degradation of actin filaments led to a dramatic decrease of hsp 27 immunostaining in core and target lesions, whereas the increased alphaBC and desmin immunostaining was found to be even more enhanced. The latter findings imply a functional diversity of both shsps with a preferential association of hsp 27 with the actin microfilament system and alphaBC with the intermyofibrillar desmin cytoskeleton in human skeletal muscle.

Actins↗
PubMed2003

Two zebrafish eIF4E family members are differentially expressed and functionally divergent.

Eukaryotic translation initiation factor 4E (eIF4E) is an essential component of the translational machinery that binds m(7)GTP and mediates the recruitment of capped mRNAs by the small ribosomal subunit. Recently, a number of proteins with homology to eIF4E have been reported in plants, invertebrates, and mammals. Together with the prototypical translation factor, these constitute a new family of structurally related proteins. To distinguish the prototypical translation factor eIF4E from other family members, it has been termed eIF4E-1 (Keiper, B. D., Lamphear, B. J., Deshpande, A. M., Jankowska-Anyszka, M., Aamodt, E. J., Blumenthal, T., and Rhoads, R. E. (2000) J. Biol. Chem. 275, 10590-10596). We describe the characterization of two eIF4E family members in the zebrafish Danio rerio. Based on their relative identities with human eIF4E-1, these zebrafish proteins are termed eIF4E-1A (82%) and eIF4E-1B (66%). eIF4E-1B, originally termed eIF4E(L), has been reported previously as the zebrafish eIF4E-1 counterpart (Fahrenkrug, S. C., Dahlquist, M. O., Clark, K., and Hackett, P. B. (1999) Differentiation 65, 191-201; Fahrenkrug, S. C., Joshi, B., Hackett, P. B., and Jagus, R. (2000) Differentiation 66, 15-22). Sequence comparisons suggest that the two genes probably evolved from a duplication event that occurred during vertebrate evolution. eIF4E-1A is expressed ubiquitously in zebrafish, whereas expression of eIF4E-1B is restricted to early embryonic development and to gonads and muscle of the tissues investigated. The ability of these two zebrafish proteins to bind m(7)GTP, eIF4G, and 4E-BP, as well as to complement yeast conditionally deficient in functional eIF4E, show that eIF4E-1A is a functional equivalent of human eIF4E-1. Surprisingly, although eIF4E-1B possesses all known residues thought to be required for interaction with the cap structure, eIF4G, and 4E-BPs, it fails to interact with any of these components, suggesting that this protein serves a role other than that assigned to eIF4E.

Adaptor Proteins, Signal Transducing↗
PubMed1975

Lactate dehydrogenase isozymes of salmonid fish. Evidence for unique and rapid functional divergence of duplicated H-4 lactate dehydrogenases.

Salmonid fish, as a result of total genome duplication, have two genes, Ldh H and Ldh H', coding for polypeptides H and H', respectively, both of which have been shown in their tetrameric forms to be immunologically related to the classical H-4 lactate dehydrogenase isozyme of higher vertebrates (Bailey, G. S., and Wilson, A. C. (1968) J. Biol. Chem. 243,5843). The H-4 and H'-4 isozymes have now been highly purified from quinnat salmon, and their chemical, physical, immunological, and catalytic properties examined, and compared to the M-4 isozyme of salmon. The two proteins H-4 and H'-4 are shown to be very similar in amino acid composition, but significant differences in a few residues suggest differences in amino acid sequences. This suggestion was born out by quantitative immunological experiments in which the H-4 and H'-4 isozymes were shown to be about as different from each other as are the H-4 lactate dehydrogenases of chicken and duck. This suggests that the gene duplication event in salmon which give rise to two Ldh H genes occurred approximately 80 to 100 million years ago. The H'-4 lactate dehydrogenase which has risen from this duplication in salmon is shown to be somewhat intermediate between H-4 and M-4 in thermal stability, and in all catalytic properties examined, including substrate optima, Michaelis constants, and susceptibility to inhibition by high levels of substrate. In particular the H'-4 isozyme is almost exactly intermediate between H-4 and M-4 in its resistance to product inhibition by lactate, the catalytic parameter suggested to be of major functional importance to M-4 lactate dehydrogenase isozymes (Stambaugh, R., and Post D. (1966) J. Biol. Chem. 241,1462). Further, tissue distribution of these isozymes in salmon and trout are shown to be unusual. The M-4 isozyme salmon and trout are shown to be unusual. The M-4 isozyme occurs in very few tissues in detectable levels. It is the H-4 and H'-4 rather than H-4 and M-4, which occur in independently variable but significant levels in most tissues examined. Thus the H'-4 isozyme, despite its very close structural similarity to H-4 appears to possess functional properties which are different from either H-4 or M-4 in salmon, and some properties are midway between the two. This finding, together with the unusual tissue distribution of these isozymes, suggests that salmon with H'-4 lactate dehydrogenase is evolving to function catalytically in the absence of a balanced H-4-M-4 isozyme complement in most tissues. This balance seems to be met in most tissues by combinations of H-4 and H'-4,

Amino Acids↗
PubMed2002

Structural origins of the functional divergence of human insulin-like growth factor-I and insulin.

Human insulin-like growth factors I and II (hIGF-I, hIGF-II) are potent stimulators of cell and growth processes. They display high sequence similarity to both the A and B chains of insulin but contain an additional connecting C-domain, which reflects their secretion without specific packaging or precursor conversion. IGFs also have an extension at the C-terminus known as the D-domain. This paper describes four homologous hIGF-1 structures, obtained from crystals grown in the presence of the detergent SB12, which reveal additional detail in the C- and D-domains. Two different detergent binding modes observed in the crystals may reflect different hIGF-I biological properties such as the interaction with IGF binding proteins and self-aggregation. While the helical core of hIGF-I is very similar to that in insulin, there are distinct differences in the region of hIGF-I corresponding to the insulin B chain C-terminus, residues B25-B30. In hIGF-I, these residues (24-29) and the following C-domain form an extensive loop protruding 20 A from the core, which results in a substantially different conformation for the receptor binding epitope in hIGF-I compared to insulin. One notable feature of the structures presented here is demonstration of peptide-bond cleavage between Ser35 and Arg36 resulting in an apparent gap between residues 35 and 39. The equivalent region of proinsulin is involved in hormone processing demanding a reassessment of the structural integrity of hIGF-I in relation to its biological function.

Amino Acid Sequence↗
PubMed1997

Characterization of a structurally and functionally diverged acyl-acyl carrier protein desaturase from milkweed seed.

A cDNA for a structurally variant acyl-acyl carrier protein (ACP) desaturase was isolated from milkweed (Asclepias syriaca) seed, a tissue enriched in palmitoleic (16:1delta9)* and cis-vaccenic (18:1delta11) acids. Extracts of Escherichia coli that express the milkweed cDNA catalyzed delta9 desaturation of acyl-ACP substrates, and the recombinant enzyme exhibited seven- to ten-fold greater specificity for palmitoyl (16:0)-ACP and 30-fold greater specificity for myristoyl (14:0)-ACP than did known delta9-stearoyl (18:0)-ACP desaturases. Like other variant acyl-ACP desaturases reported to date, the milkweed enzyme contains fewer amino acids near its N-terminus compared to previously characterized delta9-18:0-ACP desaturases. Based on the activity of an N-terminal deletion mutant of a delta9-18:0-ACP desaturase, this structural feature likely does not account for differences in substrate specificities.

Acyl Carrier Protein↗
PubMed2007

Genome evolution and functional divergence in Yersinia.

The steadily increasing number of prokaryotic genomes has accelerated the study of genome evolution; in particular, the availability of sets of genomes from closely related bacteria has made exploration of questions surrounding the evolution of pathogenesis tractable. Here we present the results of a detailed comparison of the genomes of Yersinia pseudotuberculosis IP32593 and three strains of Yersinia pestis (CO92, KIM10, and 91001). There appear to be between 241 and 275 multigene families in these organisms. There are 2,568 genes that are identical in the three Y. pestis strains, but differ from the Y. pseudotuberculosis strain. The changes found in some of these families, such as the kinases, proteases, and transporters, are illustrative of how the evolutionary jump from the free-living enteropathogen Y. pseudotuberculosis to the obligate host-borne blood pathogen Y. pestis was achieved. We discuss the composition of some of the most important families and discuss the observed divergence between Y. pseudotuberculosis and Y. pestis homologs.

Base Sequence↗
PubMed2005

Vanadium-dependent iodoperoxidases in Laminaria digitata, a novel biochemical function diverging from brown algal bromoperoxidases.

The brown alga Laminaria digitata features a distinct vanadium-dependent iodoperoxidase (vIPO) activity, which has been purified to electrophoretic homogeneity. Steady-state analyses at pH 6.2 are reported for vIPO (K (m) (I-) = 2.5 mM; k (cat) (I-) = 462 s(-1)) and for the previously characterised vanadium-dependent bromoperoxidase in L. digitata (K (m) (I-) =18.1 mM; k (cat) (I-) = 38 s(-1)). Although the vIPO enzyme specifically oxidises iodide, competition experiments with halides indicate that bromide is a competitive inhibitor with respect to the fixation of iodide. A full-length complementary ANA (cDNA) was cloned and shown to be actively transcribed in L. digitata and to encode the vIPO enzyme. Mass spectrometry analyses of tryptic digests of vIPO indicated the presence of at least two very similar proteins, in agreement with Southern analyses showing that vIPOs are encoded by a multigenic family in L. digitata. Phylogenetic analyses indicated that vIPO shares a close common ancestor with brown algal vanadium-dependent bromoperoxidases. Based on a three-dimensional structure model of the vIPO active site and on comparisons with those of other vanadium-dependent haloperoxidases, we propose a hypothesis to explain the evolution of strict specificity for iodide in L. digitata vIPO.

Amino Acid Sequence↗
PubMed1994

Functional divergence of the MAP kinase pathway. ERK1 and ERK2 activate specific transcription factors.

Growth factor-receptor interactions at the cell surface eventually leading to the transcriptional activation of immediate early genes is mediated by the mitogen-activated protein kinase (MAP kinase/MAPK) cascade. Here we show that overexpression of extracellular signal-regulated kinase 1 (ERK1) cDNA, encoding p44mapk, results in the activation of Elk-1, the serum response factor accessory protein. We also show that overexpression of ERK2, encoding p42mapk, activates Myc, but not Elk-1. Therefore, the MAP kinase cascade diverges with at least one specific target for each MAP kinase isoform and provides a novel mechanism for differential regulation of this signaling pathway.

3T3 Cells↗
PubMed1994

Structural and functional divergences of the columbid annexin I-encoding cp37 and cp35 genes.

Annexin-I proteins in the pigeon are encoded by two genes. One encodes a constitutively expressed cp37 protein, and the other encodes a major prolactin (PRL)-regulated protein (cp35). As one goal in understanding the differential regulation of these genes, we have determined a 10.8-kb genomic sequence of the cp37 gene containing 1.3 kb of 5'-flanking region and the first six exons. The promoters of cp37 and cp35 are 84% identical over the first 210 bp upstream from the transcription start point (tsp). Cell-free transcription demonstrated that this -210 region of cp37 contained an active promoter. Two nuclear protein-binding sites, which may be involved in the constitutive expression of cp37, were localized between -205 and -106 bp. PRL-dependent transcription factors bind to the -73 to -8 region of cp35, but not cp37. The sequences of these regions contain six single-base differences, which may be responsible for the genes' divergent transcriptional regulation. The 5'-flanking regions of cp37 and cp35 were cloned into a reporter plasmid and transfected into T-47D cells. Transient transfection analysis revealed that the constructs containing cp35 5'-flanking regions were inactive, whereas the cp37 promoter was constitutively active and contained both positive and negative cis-acting sequences.

Amino Acid Sequence↗
PubMed2000

Divergent functional properties of ryanodine receptor types 1 and 3 expressed in a myogenic cell line.

Of the three known ryanodine receptor (RyR) isoforms expressed in muscle, RyR1 and RyR2 have well-defined roles in contraction. However, studies on mammalian RyR3 have been difficult because of low expression levels relative to RyR1 or RyR2. Using the herpes simplex virus 1 (HSV-1) helper-free amplicon system, we expressed either RyR1 or RyR3 in 1B5 RyR-deficient myotubes. Western blot analysis revealed that RyR1- or RyR3-transduced cells expressed the appropriate RyR isoform of the correct molecular mass. Although RyR1 channels exhibited the expected unitary conductance for Cs(+) in bilayer lipid membranes, 74 of 88 RyR3 channels exhibited pronounced subconductance behavior. Western blot analysis with an FKBP12/12.6-selective antibody reveals that differences in gating behavior exhibited by RyR1 and RyR3 may be, in part, the result of lower affinity of RyR3 for FKBP12. In calcium imaging studies, RyR1 restored skeletal-type excitation-contraction coupling, whereas RyR3 did not. Although RyR3-expressing myotubes were more sensitive to caffeine than those expressing RyR1, they were much less sensitive to 4-chloro-m-cresol (CMC). In RyR1-expressing cells, regenerative calcium oscillations were observed in response to caffeine and CMC but were never seen in RyR3-expressing 1B5 cells. In [(3)H]ryanodine binding studies, only RyR1 exhibited sensitivity to CMC, but both RyR isoforms responded to caffeine. These functional differences between RyR1 and RyR3 expressed in a mammalian muscle context may reflect differences in association with accessory proteins, especially FKBP12, as well as structural differences in modulator binding sites.

Animals↗
PubMed1999

Common and diverged functions of the Drosophila gene pair D-Sp1 and buttonhead.

The Drosophila gene buttonhead (btd) is required for the formation of the mandibular, the intercalary and the antennal head segments of the embryo. The btd protein (BTD) is functionally and structurally related to the human C(2)H(2) zinc finger transcription factor Sp1. A second Sp1-like Drosophila gene, termed Drosophila Sp1 (D-Sp1), had been identified on the basis of a partial sequence showing that the gene encodes a characteristic zinc finger domain, composed of three finger motifs similar to both Sp1 and btd. D-Sp1 is located in the same cytological location as btd in chromosome band 9A on the X-chromosome. It had been proposed that D-Sp1 and btd are likely to act as a gene pair and function in a at least partially redundant manner. Here we report the molecular analysis of D-Sp1 and its expression pattern during embryonic and larval development. We show that D-Sp1 acts as a transcriptional regulator. Lack-of-function analysis combined with rescue and gain-of-function studies indicates that btd and D-Sp1 play essential and redundant roles for mechanosensory organ development. However, D-Sp1 lacks the specific features of BTD required for embryonic intercalary and antennal segment formation.

Amino Acid Sequence↗
PubMed2003

Divergent function in the crotonase superfamily: an anhydride intermediate in the reaction catalyzed by 3-hydroxyisobutyryl-CoA hydrolase.

3-Hydroxyisobutyryl-CoA hydrolase (HICH), a member of the enoyl-CoA (crotonase) superfamily, catalyzes the hydrolysis of 3-hydroxyisobutyryl-CoA to 3-hydroxyisobutyrate. Like other members of the superfamily, the sequence of HICH contains conserved sequences for an oxyanion hole that stabilizes anionic intermediates. In contrast to most members of the superfamily, the reaction catalyzed by HICH does not proceed via formation of a thioester enolate anion; instead, evidence based on substrate deuterium isotope effects, the reactivity of substrate analogues that cannot form thioester enolate anions, single-turnover experiments in H218O, and the kinetic phenotypes of site-directed mutants provide evidence for a mechanism involving the formation of an anhydride intermediate involving Glu143 in the active site. In the reactions catalyzed by many members of the superfamily, homologues of Glu143 abstract the alpha proton of the thioester substrate to generate the thioester enolate anion intermediate. Presumably, one or more of the anionic tetrahedral intermediates on the HICH reaction coordinate are stabilized by the oxyanion hole. Thus, we conclude that the conserved oxyanion hole in this superfamily can be used to stabilize a variety of anionic intermediates.

Anhydrides↗
PubMed2005

New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions.

Understanding the factors that influence T helper 1 (T(H)1)- and T(H)2-cell responses has been one of the main focuses of immunology for almost 20 years. Whereas the central role of interleukin-12 (IL-12) in the generation of T(H)1 cells has long been appreciated, subsequent studies indicated that IL-23 and IL-27, two cytokines that are closely related to IL-12, also regulate T(H)1-cell responses. However, as discussed in this article, it is now recognized that the ability of IL-23 to stimulate a unique T-cell subset to produce IL-17 has a dominant role in autoimmune inflammation. By contrast, IL-27 has a role in limiting the intensity and duration of adaptive immune responses.

Animals↗
PubMedDate not supplied

Conserved and divergent functions of Drosophila atonal, amphibian, and mammalian Ath5 genes.

Insect and vertebrate eyes differ in their formation, cellular composition, neural connectivity, and visual function. Despite this diversity, Drosophila atona and its vertebrate Ortholog in the eye, Ath5, each regulate determination of the first retinal neuron class-R8 photo-receptors and retinal ganglion cells (RGCs)-in their respective organisms. We have performed a cross-species functional comparison of these genes. In ato mutant Drosophila, ectopic Xenopus Ath5 (Xath5) rescues photoreceptor cell development comparably with atonaI. In contrast, mouse Ath5 (Math5) induces formation of very few ommatidia, and most of these lack R8 cells. In the developing frog eye, ectopic atonal, like Xath5, promotes the differentiation RGCs. Despite strong conservation of atonaI, Xath5, and Math5 structure and shared function, other factors must contribute to the species specificity of retinal neuron determination. These observations suggest that the atonaI family may occupy a position in a gene hierarchy where differences in gene regulation or function can be correlated with evolutionary diversity of eye development.

Amino Acid Sequence↗