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PubMed1996

Structural analysis of a human glial variant laminin.

Astrocytes secrete laminin-like molecules in culture and may represent a major source of laminin in the developing central nervous system, yet these laminins have not been extensively characterized. We previously reported the presence of an astrocyte-derived variant laminin in media conditioned by human U251 MG astrocytoma cells. This laminin was partially purified in a highly anionic Mono Q fraction with strong adhesion activity for fibroblasts and glial cells (Aukhil et al. (1990) Matrix 10: 98-111). We now show that glial laminin could be dissociated from an anionic species, perhaps an approximately 400-kDa keratan sulfate proteoglycan present in the preparation, by a second round of Mono Q anion exchange chromatography in the presence of 6 M urea. Cell adhesion activity remained tightly associated with laminin-containing fractions, suggesting that glial laminin was responsible for the adhesion activity in the original preparation. Immunochemical and SDS-PAGE gel analyses of laminin heterotrimers demonstrated that glial laminin contained the beta 2 and gamma 1 chains in disulfide-bonded heterotrimeric complexes with a 360-kDa chain, a 320-kDa chain, or a postulated approximately 200-kDa chain. While these chains were not recognized by antibodies directed against the alpha 1-, alpha 2-, or alpha 3-related laminin chains, rotary shadowed glial laminin molecules appeared to contain alpha chains, as judged by the presence of an apparent G-domain terminating the long arm of each laminin molecule. These findings suggest that glial laminin contains one or more variant alpha chains, perhaps related to one of the more recently described alpha chains, alpha 3B, alpha 4, or alpha 5. Together our results implicate human U251 MG glial laminin as a previously uncharacterized laminin isoform with strong adhesive activity for fibroblasts and glial cells.

Anion Exchange Resins↗
PubMed1993

Primary and secondary structure of a 360-nucleotide isolate of potato spindle tuber viroid.

Full-length complementary DNAs (cDNA) of a mild (KF5) and a severe (S-PSTVd) isolate of potato spindle tuber viroid (PSTVd) were constructed. DNA sequencing of four KF5 cDNA clones (M3, M4, M5, and M7) revealed that KF5 is comprised of 360 nucleotides. By comparison, all three cDNA clones (S2, S9, and S10) of S-PSTVd possess 359 nucleotides. Sequence microheterogeneity was observed among the KF5 cDNA clones. Clone M5 differs from mild PSTVd isolate KF6 by a U-to-A transversion at position 303 followed by an A addition at the lower half of the "virulence-modulating" (VM) region. These changes modified the PSTVd consensus sequence of the VM region from 5' UCUAUCU 3' to 5' UCAAAUCU 3'. Additionally, clones M4 and M7 have a G-to-A transition at position 65 of the pathogenic domain, and M3 has a G-to-A transition at position 133 of the variable domain. The sequence of the three cDNA clones of S-PSTVd was identical to that of PSTVd isolate 440-1. An improved computer program was used to predict the secondary structure of the above two sequence variants as well as that of other PSTVd variants of which the structure has been reported previously. The data provides support for the hypothesis that increasing thermodynamic instability of the VM region is correlated with increasing virulence of the respective naturally occurring PSTVd isolate.

Base Sequence↗
PubMed2003

Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants.

Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a neuron-specific ubiquitin recycling enzyme. A mutation at residue 93 and polymorphism at residue 18 within human UCH-L1 are linked to familial Parkinson's disease and a decreased Parkinson's disease risk, respectively. Thus, we constructed recombinant human UCH-L1 variants and examined their structure (using circular dichroism) and hydrolase activities. We confirmed that an I93M substitution results in a decrease in kcat (45.6%) coincident with an alteration in alpha-helical content. These changes may contribute to the pathogenesis of Parkinson's disease. In contrast, an S18Y substitution results in an increase in kcat (112.6%) without altering the circular dichroistic spectrum. These data suggest that UCH-L1 hydrolase activity may be inversely correlated with Parkinson's disease risk and that the hydrolase activity is protective against the disease. Furthermore, we found that oxidation of UCH-L1 by 4-hydroxynonenal, a candidate for endogenous mediator of oxidative stress-induced neuronal cell death, results in a loss of hydrolase activity. Taken together, these results suggest that further studies of altered UCH-L1 hydrolase function may provide new insights into a possible common pathogenic mechanism between familial and sporadic Parkinson's disease.

Aldehydes↗
PubMed1996

Crystal structures of guinea-pig, goat and bovine alpha-lactalbumin highlight the enhanced conformational flexibility of regions that are significant for its action in lactose synthase.

BACKGROUND: The regulation of milk lactose biosynthesis is highly dependent on the action of a specifier protein, alpha-lactalbumin (LA). Together with a glycosyltransferase, LA forms the enzyme complex lactose synthase. LA promotes the binding of glucose to the complex and facilitates the biosynthesis of lactose. To gain further insight into the molecular basis of LA function in lactose synthase we have determined the structures of three species variants of LA. RESULTS: The crystal structures of guinea-pig, goat and a recombinant from of bovine LA have been determined using molecular replacement techniques. Overall, the structures are very similar and reflect their high degree of amino acid sequence identity (66-94%). Nonetheless, the structures show that a portion of the molecule (residues 105-110), known to be important for function, exhibits a variety of distinct conformers. This region lies adjacent to two residues (Phe31 and His32) that have been implicated in monosaccharide binding by lactose synthase and its conformation has significant effects on the environments of these functional groups. The crystal structures also demonstrate that residues currently implicated in LA's modulatory properties are located in a region of the structure that has relatively high thermal parameters and is therefore probably flexible in vivo. CONCLUSIONS: LA's proposed interaction site for the catalytic component of the lactose synthase complex is primarily located in the flexible C-terminal portion of the molecule. This general observation implies that conformational adjustments may be important for the formation and function of lactose synthase.

Animals↗
PubMed2001

Li24[MnN3]3N2 and Li5[(Li1-xMnx)N]3, two intermediates in the decomposition path of Li7[MnN4] to Li2[(Li1-xMnx)N]: an experimental and theoretical study.

The crystal structure of Li7[Mn(V)N4] was re-determined. Isolated tetrahedral [Mn(V)N4](7-) ions are arranged with lithium cations to form a superstructure of the CaF2 anti-type (P4bar3n, No. 218, a = 956.0(1) pm, Z = 8). According to measurements of the magnetic susceptibility, the manganese (tetrahedral coordination) is in a d(2) S = 1 state. Thermal treatment of Li7[Mn(V)N4] under argon in the presence of elemental lithium at various temperatures leads to Li24[Mn(III)N3]3N2, Li5[(Li1-xMnx)N]3, and Li2[(Li1-xMn(I)x)N], respectively. Li24[Mn(III)N3]3N2 (P3bar1c, No. 163, a = 582.58(6) pm, c = 1784.1(3) pm, Z = 4/3) crystallizes in a trigonal unit cell, containing slightly, but significantly nonplanar trigonal [MnN3](6-) units with C3v symmetry. Measurements of the magnetic susceptibility reveal a d(4) S = 1 spin-state for the manganese (trigonal coordination). Nonrelativistic spin-polarized DFT calculations with different molecular models lead to the conclusion that restrictions in the Li-N substructure are responsible for the distortion from planarity of the [Mn(III)N3](6-). Li5[(Li1-xMnx)N]3 (x = 0.59(1), P6bar2m, No. 189, a = 635.9(3) pm, c = 381.7(2) pm, Z = 1) is an isotype of Li5[(Li1-xNix)N]3 with manganese in an average oxidation state of about +1.6. The crystal structure is a defect variant of the alpha-Li3N structure type with the transition metal in linear coordination by nitrogen. Li2[(Li1-xMn(I)x)N] (x = 0.67(1), P6/mmm, No. 191, a = 371.25(4) pm, c = 382.12(6) pm, Z = 1) crystallizes in the alpha-Li3N = Li2[LiN] structure with partial substitution of the linearly nitrogen-coordinated Li-species by manganese(I). Measurements of the magnetic susceptibility are consistent with manganese (linear coordination) in a low-spin d(6) S = 1 state.

Journal Article↗
PubMed2004

R(6)TT'(2), new variants of the Fe(2)P structure type. Sc(6)TTe(2) (T = Ru, Os, Rh, Ir), Lu(6)MoSb(2), and the anti-typic Sc(6)Te(0.80)Bi(1.68).

The Fe(2)P structure (P62m) features two 3-fold Fe positions and both 2-fold and 1-fold P sites, and variations in occupancies of the latter pair yield the reported diversity of results. The known Sc(6)TTe(2) examples for T = Fe-Ni are herein extended to four heavier transition metal T derivatives. An attempt to synthesize bismuth analogues led to the novel inverse derivative in which fractional Te (vice T) occupies the smaller tricapped trigonal prismatic (TTP) Sc polyhedron, and Bi rather than Te occurs in the larger TTP of Sc, with parallel reversal of polarity in the bonding. The reported Lu(8)Te, which is distributed as Lu(6)TeLu(2), is the only example in which a transition metal occupies the normal 2-fold P or Te non-metal position, with corresponding large effects on the bonding. Lutetium otherwise does not form R(6)TTe(2) analogues, but the novel Lu(6)MoSb(2) isotype occurs instead. Extended Hückel calculations are presented for five examples, and the structural and bonding regularities and varieties are discussed further.

Journal Article↗
PubMed2002

Childhood epidermolysis bullosa acquisita: a novel variant with reactivity to all three structural domains of type VII collagen.

Most patients with epidermolysis bullosa acquisita develop an autoimmune response to the non-collagenous (NC) 1 domain of type VII collagen. We report a 4-year-old girl of white European descent presenting with widespread blistering disease involving the face, hands, genital area and oral mucosa. Histopathology revealed subepidermal blisters, and linear deposits of IgG and C3 were seen along the dermal-epidermal junction on direct immunofluorescence (IF) microscopy of a perilesional skin biopsy. On indirect IF microscopy, circulating autoantibodies exclusively stained the dermal side of 1 mol L-1 NaCl-split skin. The patient's IgG autoantibodies labelled a 290-kDa protein on Western blotting of dermal extracts, and reacted with the NC1, NC2 and triple helical domains of type VII collagen on immunoblotting of recombinant and cell-derived fragments obtained by pepsin and collagenase digestion of the full-length protein. Oral methylprednisolone and dapsone led to clearance of lesions, which healed with mild scarring and milia formation. Treatment was discontinued after 1 year and the patient has now been in remission for more than 3 years.

Autoantibodies↗
PubMed2002

Variant subunit specificity in the quaternary structure of Artemia hemoglobin.

The brine shrimp Artemia has three extracellular hemoglobins (Hbs) that are developmentally expressed and exhibit distinct oxygen-binding characteristics (Heip, Moens, and Kondo 1978; Heip et al. 1978 ). These Hbs are composed of two polymers, each of which comprises nine covalently linked globin domains. Although the cDNA sequences of two nine-domain globins from Artemia have been published, there is evidence for the existence of further expressed globin genes (Manning, Trotman, and Tate 1990 ). In the present study extensive analysis at the cDNA and genomic levels was performed in order to determine the globin gene copy number in Artemia. Sequence and Southern analysis suggest that four Hb polymers (T1, T2, C1, and C2) are expressed in Artemia. In addition, there is also at least one globin pseudogene. Protein sequencing of the native Hbs revealed that there are limitations on which two polymers can associate. The composition of the Hbs has been determined to be: Hb I, C1C2; Hb II, C1T2; and Hb III, T1T2. These pairings allow the levels of the three Artemia Hbs to be regulated independently by polymer expression alone, therefore explaining the previously inconsistent developmental and hypoxia-induced expression patterns.

Animals↗
PubMed1984

The genome structure of cowpox virus white pock variants.

A previous report described restriction endonuclease analysis of white pock variants of red cowpox virus and their characterization as deletion mutants lacking certain sequences including the repetition from one specific terminus of the wild-type genome. Further analysis has confirmed the terminal deletion but demonstrated that this is compensated at the site of deletion by the presence of an inverted duplication of a variable amount of sequence from the opposite terminus, with the effect of restoring a terminal repetition and the covalent, terminal crosslink. Nine of 11 white pock variants showed a similar deletion of about 21 Mdal mapping contiguously from the right-hand terminus and extending into a 2.4 Mdal restriction fragment. Two white variants showed larger deletions of about 24 and 27 Mdal respectively. These deletions were compensated by a copy of sequences from the opposite terminus which ranged in size from 3 to 27 Mdal. No terminal deletions smaller than 21 Mdal were observed in cowpox white variants or in clones retaining the red phenotype. In contrast with other orthopoxviruses, no deletions involving the left-hand terminus were found. Some independent white isolates had similar sizes of sequence copied from the opposite terminus, but some sibling clones from a single, pock-purified white isolate with the same size of deletion had different sizes of duplicated sequence. Other siblings isolated from an independent, three times pock-purified white clone, itself derived from a single parental red pock, differed from each other in the size of both the deletion and the duplicated sequence. These observations suggest preference for deletion in a particular region, conjunction of the genome termini during DNA replication and a requirement for the preservation of symmetrical termini in orthopoxvirus genome function.

Base Sequence↗
PubMed2003

Manganese antimony diselenide iodide, MnSbSe2I.

MnSbSe(2)I contains layers parallel to the bc plane that consist of edge- and corner-sharing MnSe(6/2) and MnSe(2/2)I(4/2) octahedra. Sb atoms are located between these layers and form SbSe(3) trigonal pyramids. Owing to the off-center placement of the Sb atom and the inequivalence of the two crystallographically independent Mn atoms, the monoclinic MnSbSe(2)I structure is a distorted variant of the orthorhombic UFeS(3) structure type.

Journal Article↗
PubMed1998

Herpes simplex virus glycoprotein D can bind to poliovirus receptor-related protein 1 or herpesvirus entry mediator, two structurally unrelated mediators of virus entry.

Several cell membrane proteins have been identified as herpes simplex virus (HSV) entry mediators (Hve). HveA (formerly HVEM) is a member of the tumor necrosis factor receptor family, whereas the poliovirus receptor-related proteins 1 and 2 (PRR1 and PRR2, renamed HveC and HveB) belong to the immunoglobulin superfamily. Here we show that a truncated form of HveC directly binds to HSV glycoprotein D (gD) in solution and at the surface of virions. This interaction is dependent on the native conformation of gD but independent of its N-linked glycosylation. Complex formation between soluble gD and HveC appears to involve one or two gD molecules for one HveC protein. Since HveA also mediates HSV entry by interacting with gD, we compared both structurally unrelated receptors for their binding to gD. Analyses of several gD variants indicated that structure and accessibility of the N-terminal domain of gD, essential for HveA binding, was not necessary for HveC interaction. Mutations in functional regions II, III, and IV of gD had similar effects on binding to either HveC or HveA. Competition assays with neutralizing anti-gD monoclonal antibodies (MAbs) showed that MAbs from group Ib prevented HveC and HveA binding to virions. However, group Ia MAbs blocked HveC but not HveA binding, and conversely, group VII MAbs blocked HveA but not HveC binding. Thus, we propose that HSV entry can be mediated by two structurally unrelated gD receptors through related but not identical binding with gD.

Amino Acid Sequence↗
PubMed2006

Variant BDNF (Val66Met) impact on brain structure and function.

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are a unique family of polypeptide growth factors that influence differentiation and survival of neurons in the developing nervous system. In adults, BDNF is important in regulating synaptic plasticity and connectivity in the brain. Recently, a common single-nucleotide polymorphism in the human BDNF gene, resulting in avaline to methionine substitution in the prodomain (Val66Met), has been shown to lead to memory impairment and susceptibility to neuropsychiatric disorders. An understanding of how this naturally occurring polymorphism affects behavior, anatomy, and cognition in adults is an important first step in linking genetic alterations in the neurotrophin system to definable biological outcomes in humans. We review the recent literature linking this BDNF polymorphism to cognitive impairment in the context of in vitro and transgenic animal studies that have established BDNF's central role in neuronal functioning in the adult brain.

Animals↗
PubMed1976

[Mucoepidermoid tumors of the bronchi].

A total of 14 observations on mucoepidermoid tumours of the bronchi were studied. Patients were of the age of 29-75 years. Nine tumours were exophytic, 3-- endobronchial, 2--of the type "Iceberg". A definite interdependence was observed between the anatomic form of the tumours and histological structure thereof. All the variants of the multi-stratified structures (pseudoepidermoid, spindle-cellular, clear-cellular, and others) were characterized by the absence of cornification, and they fully comply with the notion of ateleplasia suggested by V.G. Garshin. Similarly, in mucigenesis there was not observed metaplasia, but maturation of cells in the direction natural for the respiratory epithelium. Mucigenesis could be realized in two ways: in glandular tubes or by mucification of individual cells of the pseudoepidermoid layers. In the latter case the polar differentiation of cells was absent. Mucoepidermoid tumours may develop both from mucous glands and from tegmental epithelium of the bronchi.

Adolescent↗