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PubMed1994

On the suitability of urethane bonds between the carrier and the drug moiety in poly(ethyleneglycol)-based oligomeric prodrugs.

Some poly(ethyleneglycol) derivatives of propranolol were prepared, in which the drug molecule was linked to the oligomeric carrier via urethane bonds in order to study the suitability of this bond as a linkage between the carrier and the drug moiety in oligomeric prodrugs. For comparison purposes also ethanol- and butanol-based prodrugs of propranolol were prepared, with the same linkage between drug and promoiety. The urethane compounds were obtained by condensation via N,N'-carbonyldiimidazole. None of these compounds gave rise to appreciable blood concentrations of propranolol after oral administration, thus suggesting in this particular case, a relative in vivo resistance of urethane bonds towards cleavage.

Administration, Oral↗
PubMed2005

Physicochemical characteristics of soluble oligomeric Abeta and their pathologic role in Alzheimer's disease.

Extracellular fibrillar amyloid deposits are prominent and universal Alzheimer's disease (AD) features, but senile plaque abundance does not always correlate directly with the degree of dementia exhibited by AD patients. The mechanism(s) and dynamics of Abeta fibril genesis and deposition remain obscure. Enhanced Abeta synthesis rates coupled with decreased degradative enzyme production and accumulating physical modifications that dampen proteolysis may all enhance amyloid deposit formation. Amyloid accumulation may indirectly exert the greatest pathologic effect on the brain vasculature by destroying smooth muscle cells and creating a cascade of negative impacts on cerebral blood flow. The most visible manifestation of amyloid dis-equilibrium could actually be a defense mechanism employed to avoid serious vascular wall degradation while the major toxic effects to the gray and white matter neurons are mediated by soluble oligomeric Abeta peptides with high beta-sheet content. The recognition that dynamic soluble oligomeric Abeta pools exist in AD and are correlated to disease severity led to neurotoxicity and physical conformation studies. It is now recognized that the most basic soluble Abeta peptides are stable dimers with hydrophobic regions sequestered from the aqueous environment and are capable of higher order aggregations. Time course experiments employing a modified ELISA method able to detect Abeta oligomers revealed dynamic intermolecular interactions and additional experiments physically confirmed the presence of stable amyloid multimers. Amyloid peptides that are rich in beta-sheet structure are capable of creating toxic membrane ion channels and a capacity to self-assemble as annular structures was confirmed in vitro using atomic force microscopy. Biochemical studies have established that soluble Abeta peptides perturb metabolic processes, provoke release of deleterious reactive compounds, reduce blood flow, induce mitochondrial apoptotic toxicity and inhibit angiogenesis. While there is no question that gross amyloid deposition does contribute to AD pathology, the destructive potential now associated with soluble Abeta suggests that treatment strategies that target these molecules may be efficacious in preventing some of the devastating effects of AD.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2003

Oligomerization of RANTES is required for CCR1-mediated arrest but not CCR5-mediated transmigration of leukocytes on inflamed endothelium.

Chemokines control inflammatory leukocyte recruitment. The propensity of chemokines such as CC chemokine ligand 5 (CCL5)/RANTES (regulated on activation, normal T cell expressed and secreted) to bind to glycosaminoglycans and to form higher order oligomers has been shown to be essential for its in vivo activity. However, the specific functional relevance of RANTES oligomerization for distinct steps of leukocyte recruitment on inflamed endothelium mediated by the RANTES receptors CC chemokine receptor 1 (CCR1) and CCR5 remains undefined. We studied RANTES mutants with deficient oligomerization in an assay in which recruitment of monocytes and CD45RO+ CD4+ T cells is triggered by RANTES immobilized on activated endothelium under flow conditions. Notably, the formation of higher order RANTES oligomers was crucial for CCR1-mediated arrest but not for CCR5-mediated spreading/transmigration in flow or transendothelial chemotaxis of leukocytes. Efficient leukocyte arrest in flow but not transmigration may thus require the presentation of RANTES oligomers to bridge surface-bound RANTES and CCR1.

Cell Movement↗
PubMed2005

Oligomeric protein structure networks: insights into protein-protein interactions.

BACKGROUND: Protein-protein association is essential for a variety of cellular processes and hence a large number of investigations are being carried out to understand the principles of protein-protein interactions. In this study, oligomeric protein structures are viewed from a network perspective to obtain new insights into protein association. Structure graphs of proteins have been constructed from a non-redundant set of protein oligomer crystal structures by considering amino acid residues as nodes and the edges are based on the strength of the non-covalent interactions between the residues. The analysis of such networks has been carried out in terms of amino acid clusters and hubs (highly connected residues) with special emphasis to protein interfaces. RESULTS: A variety of interactions such as hydrogen bond, salt bridges, aromatic and hydrophobic interactions, which occur at the interfaces are identified in a consolidated manner as amino acid clusters at the interface, from this study. Moreover, the characterization of the highly connected hub-forming residues at the interfaces and their comparison with the hubs from the non-interface regions and the non-hubs in the interface regions show that there is a predominance of charged interactions at the interfaces. Further, strong and weak interfaces are identified on the basis of the interaction strength between amino acid residues and the sizes of the interface clusters, which also show that many protein interfaces are stronger than their monomeric protein cores. The interface strengths evaluated based on the interface clusters and hubs also correlate well with experimentally determined dissociation constants for known complexes. Finally, the interface hubs identified using the present method correlate very well with experimentally determined hotspots in the interfaces of protein complexes obtained from the Alanine Scanning Energetics database (ASEdb). A few predictions of interface hot spots have also been made based on the results obtained from this analysis, which await experimental verification. CONCLUSION: The construction and analysis of oligomeric protein structure networks and their comparison with monomeric protein structure networks provide insights into protein association. Further, the interface hubs identified using the present method can be effective targets for interface de-stabilizing mutations. We believe this analysis will significantly enhance our knowledge of the principles behind protein association and also aid in protein design.

Animals↗
PubMed2004

Oligomerization state-dependent hyperlipidemic effect of angiopoietin-like protein 4.

Angiopoietin-like protein 4 (Angptl4) is the second member of the angiopoietin-like family of proteins previously shown to increase plasma triglyceride (TG) levels in vivo. We recently reported that Angptl4 is a variable-sized oligomer formed by intermolecular disulfide bonds and undergoes regulated proteolytic processing upon secretion. We now show that adenoviral overexpression of Angptl4 potently increases plasma TG levels by a mechanism independent of food intake or hepatic VLDL secretion. We determined that cysteine residues at positions 76 and 80 of Angptl4, conserved among mouse, rat, and human, are required to form higher order structures. By generating adenoviral expression vectors of Angptl4 containing different epitope tags at both N and C termini, we show that loss of oligomerization results in decreased stability of the N-terminal coiled-coil domain of Angptl4 as well as decreased ability to increase plasma TG levels, suggesting that intermolecular disulfide bond formation plays important roles in determining the magnitude of the hyperlipidemic effect of Angptl4. Because Angptl4 is more potent than Angptl3 in increasing plasma TG levels in mice, inappropriate oligomerization of Angptl4 could be associated with disorders of lipid metabolism in vivo.

Adenoviridae↗
PubMed2005

Effect of Walker A mutation (K86M) on oligomerization and surface targeting of the multidrug resistance transporter ABCG2.

The ATP binding cassette (ABC) half-transporter ABCG2 (MXR/BCRP/ABCP) is associated with mitoxantrone resistance accompanied by cross-resistance to a broad spectrum of cytotoxic drugs. Here we investigate the functional consequences of mutating a highly conserved lysine in the Walker A motif of the nucleotide binding domain (NBD) known to be critical for ATP binding and/or hydrolysis in ABC transporters. The mutant (ABCG2-K86M) was inactive as expected but was expressed at similar levels as the wild-type (wt) protein. The mutation did not affect the predicted oligomerization properties of the transporter; hence, co-immunoprecipitation experiments using differentially tagged transporters showed evidence for oligomerization of both ABCG2-wt and of ABCG2-wt with ABCG2-K86M. We also obtained evidence that both ABCG2-wt and ABCG2-K86M exist in the cells as disulfide-linked dimers. Moreover, measurement of prazosin-stimulated ATPase activity revealed a dominant-negative effect of ABCG2-K86M on ABCG2-wt function in co-transfected HEK293 cells. This is consistent with the requirement for at least two active NBDs for transporter activity and suggests that the transporter is a functional dimer. Finally, we analyzed targeting of ABCG2-wt and ABCG2-K86M and observed that they localize to two distinct subcellular compartments: ABCG2-wt targets the cell surface whereas ABCG2-K86M is targeted to the Golgi apparatus followed by retrieval to the endoplasmic reticulum. This suggests an as yet unknown role of the NBDs in assisting proper surface targeting of ABC transporters.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2001

Evidence for separate ND10-binding and homo-oligomerization domains of Sp100.

Nuclear domains called ND10 or PML nuclear bodies consist of an aggregation of several proteins, most notably PML and Sp100. PML is essential in the nucleation and formation of ND10 as well as in the recruitment of other ND10-associated proteins such as Daxx, pRb, BLM and Sp100. In cells induced to overexpress Sp100, ND10 binding of Sp100 was saturable and excess Sp100 formed new aggregation sites devoid of other ND10-associated proteins, suggesting that homo-oligomerization is the basis for aggregation. To determine whether Sp100 binds to ND10 through hetero- or oligomerization, Sp100 deletion variants fused with GFP were transfected into cells with and without endogenous Sp100, and the localization of the GFP-labeled fragments was determined relative to ND10. Amino acids 29-152 were sufficient for deposition of the GFP-labeled fragments at ND10 in the absence of endogenous Sp100 (heterologous binding) and for self-aggregation (formation of new Sp100 deposits). None of the shorter fragments was deposited at ND10 or self-aggregated. The 29-152 amino acid fragment and some larger fragments, but not the full-size Sp100, induced elongation of ND10, which at their ends contain only Sp100, probably due to self-aggregation. By fusing a peptide consisting of the p53-binding domain from hMDM2 to the Sp100(29-152) fragment, this self-aggregation could be blocked while retaining the limited ND10 binding capacity, indicating that the Sp100 self-aggregation domain and the ND10 binding domain are separate entities. This fusion peptide was used to demonstrate the potential of ND10 to recruit p53 as a protein not usually present at this site. Such deposited p53 was protected from turnover. The capacity of ND10 to recruit Sp100 may serve primarily to reduce its availability.

Antigens, Nuclear↗
PubMed2005

Inactivation of Vibrio vulnificus hemolysin by oligomerization but not proteolysis.

Vibrio vulnificus extracellular protease (VvpE) is believed to destroy its hemolysin (VvhA) in the late growth phase, without obvious experimental evidence. So, we attempted to elucidate the mechanism. The hemolytic activity steeply increased with the expression of the VvhA in the early growth phase, and then abruptly declined with the expression of VvpE in the late growth phase. However, the VvhA activity also abruptly declined in a VvpE-deficient mutant. In Western blot, the degradation of VvhA was not observed; instead, the oligomerization of VvhA increased with the concomitant loss of hemolytic activity. These results evidently indicate that the inactivation of VvhA is due to the novel oligomerization of VvhA by unknown mechanism, but not to the destruction of VvhA by VvpE, so that the routine functional assay measuring hemolytic activity cannot reflect the actual production of VvhA.

Biopolymers↗
PubMed2005

Effects of phospholipids on the oligomeric state of phospholamban of the cardiac sarcoplasmic reticulum.

BACKGROUND: Phospholamban is a reversible inhibitor of the Ca(2+)-ATPase of the cardiac sarcoplasmic reticulum (SR) and contributes to the regulation of heart muscle contractility. Because only the monomeric form, not the pentameric form, of phospholamban inhibits the Ca2+-pumping activity of the SR, it is important to understand the dynamic equilibrium between these 2 forms. METHODS AND RESULTS: The effects of various detergents and phospholipids on the oligomeric state of phospholamban were examined. Among the detergents examined, 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate (CHAPS) stabilized the pentameric form whereas octylglucoside was an effective inducer of dissociation into the monomer. On the basis of these properties of the 2 detergents, the effects of various phospholipids on the oligomeric state of phospholamban with the use of mixed micelles containing octylglucoside or CHAPS were examined. Among the 8 phospholipids examined, phosphatidic acid was an effective inducer of pentamer dissociation, whereas the other phospholipids exhibited pentamer-stabilizing activity. Lysophosphatidylcholine, lysophosphatidylethanolamine, and phosphatidylglycerol were highly effective stabilizers of the pentamer. CONCLUSIONS: The phospholipids in the SR membrane are important determinants of the equilibrium between the monomeric and pentameric forms of this protein. The results suggest that the metabolism of phospholipids in the cardiac SR may contribute to regulation of heart muscle contractility by shifting this equilibrium.

Animals↗
PubMed2005

Two novel cyclodextrin-degrading enzymes isolated from thermophilic bacteria have similar domain structures but differ in oligomeric state and activity profile.

In this paper, we present the expression and characterization of two novel enzymes from the alpha-amylase family exhibiting cyclomaltodextrinase specificity. The nucleotide sequences encoding the enzymes were isolated from the genomic DNA of two thermophilic bacterial strains originating from Icelandic hot springs and belonging to the genera Anoxybacillus (AfCda13) and Laceyella (LsCda13). The genes were amplified using a consensus primer strategy utilizing two of the four conserved regions present in glycoside hydrolase family 13. No identifiable signal peptides were present in open reading frames encoding the enzymes, indicating an intracellular location of both enzymes, and their physiological function to be intracellular cyclodextrin degradation. The domain structures of both enzymes were also similar, including an N-terminal domain, the catalytic module composed of the A- and B-domains, and a C-terminal domain. Despite the similarity in domain composition, the two enzymes displayed differences in the oligomeric state with AfCda13 being a dimeric protein, whereas LsCda13 was monomeric. The two enzymes also displayed significantly different activity profiles, despite being active on the same range of substrates. It was shown that the enzyme displaying the highest activity on cyclodextrin was dimeric (AfCda13). Moreover, a fraction of the dimeric enzyme could be converted to a monomeric state in the presence of KCl and this fraction retained only 23% of its activity on alpha-cyclodextrin while its activity on starch was not significantly affected, indicating that the oligomeric state is an important factor for a high activity on cyclodextrin substrates.

Amino Acid Sequence↗
PubMed1998

Chemical modification of the hemolytic lectin CEL-III by succinic anhydride: involvement of amino groups in the oligomerization process.

CEL-III is a Ca(2+)-dependent lectin from a marine invertebrate, Cucumaria echinata, which shows strong hemolytic activity toward human and rabbit erythrocytes. After binding to carbohydrate receptors, CEL-III oligomerizes in the erythrocyte membrane to form ion-permeable pores, leading to the colloid osmotic rupture of the cells. Since hemolysis was greatly increased in the alkaline pH, especially above pH 9, involvement of amino groups of CEL-III in its hemolytic activity was evaluated using chemical modification by succinic anhydride. After modification of 7 amino groups per protein molecule, the hemolytic activity of CEL-III was reduced to 23% of the native protein, but hemagglutinating and carbohydrate-binding activities were only slightly affected even after modification of 14 amino groups. A circular dichroism spectrum of modified CEL-III showed almost no change in the secondary structure from that of the native protein, indicating that the decrease of hemolytic activity was not caused by partial unfolding of the protein. Immunoblotting analysis of the erythrocyte membrane treated with modified CEL-III showed a decrease in the formation of CEL-III oligomer in the membrane in parallel with the decrease in hemolytic activity. These results suggest that amino groups of CEL-III are involved in its oligomerization in the cell membrane, and their modification leads to inactivation of the protein without much influence on the carbohydrate-binding activity.

Amino Acids↗
PubMed2003

Root growth-promoting activity of unsaturated oligomeric uronates from alginate on carrot and rice plants.

The root elongation activity of unsaturated oligomeric uronates from alginate on carrot and rice plants was investigated. Unsaturated oligomeric uronates were prepared by digesting polymannuronate (PM) and polyguluronate (PG) with an alginate lyase purified from Pseudoalteromonas sp. strain No. 272. The root elongation activity was measured by elongation in length of carrot- and rice-excised root incubated in the B5-medium containing 0.8% agar in the dark. PM and PG showed no activity, but the enzymatic digestion mixtures of PG had promoting activity on roots of both plants at a final concentration of 0.5 mg/ml. The maximum activity was obtained at 0.75 mg/ml. The dependence of activity on degree of polymerization of the uronates was tested and the pentamer was most active, but the mechanism of the action of unsaturated uronates on the cells remains to be solved.

Alginates↗
PubMed1993

Abnormal multimeric and oligomeric composition is associated with enhanced endothelial expression of von Willebrand factor in pulmonary hypertension.

Abnormalities in endothelial von Willebrand factor (vWF) structure have been reported in pulmonary hypertension. These include loss of high molecular weight plasma multimers, resulting in decreased biologic activity. If endothelial processing of vWF is altered in this disorder, abnormalities in oligomeric composition may also be expected. We examined this possibility in ten adult patients with primary pulmonary hypertension. Enhanced endothelial vWF expression in these patients was indicated by increased plasma levels of vWF antigen (vWF:Ag) (214 +/- 91 vs 99 +/- 51 percent activity in controls, p < 0.001) and intense immunoperoxidase stain of pulmonary arterial endothelium for vWF (autopsy, 1 patient). Plasma from these patients also had a decreased capacity of inducing platelet aggregation in the presence of ristocetin, relative to vWF:Ag levels (57 +/- 20 percent activity). In addition to mild loss of the largest multimers, changes in oligomeric composition of plasma vWF were observed in most patients using both agarose and polyacrylamide gel electrophoresis. These included decreased concentration of dimeric (470 kDa) vWF in most patients, variable concentration of the 860-kDa fraction, and a relative decrease in subunit (223 kDa) density in subjects with elevated vWF:Ag. These findings provide additional information on the mechanisms responsible for endothelial production of dysfunctional vWF in patients with pulmonary hypertension.

Adult↗
PubMed2005

Determination of Peptide oligomerization state using rapid photochemical crosslinking.

The assembly of the amyloid beta-protein (Abeta) into neurotoxic oligomers and fibrils is a seminal pathogenic process in Alzheimer's disease (AD). Understanding the mechanisms of Abeta assembly could prove useful in the identification of therapeutic targets. Owing to the metastable nature of Abeta oligomers, it is difficult to obtain interpretable data through application of classical methods, such as electrophoresis, chromatography, fluorescence, and light scattering. Here, we apply the method Photo-Induced Crosslinking of Unmodified Proteins (PICUP) to the study of Abeta oligomerization. This method directly produces covalent bonds among unmodified polypeptide chains through in situ generation of peptide free radicals. PICUP provides a snapshot of the native oligomerization state of proteins and can be used for assembly state analysis of a wide variety of peptides and proteins.

Amyloid beta-Peptides↗
PubMed2006

Oligomeric states of proteins determined by size-exclusion chromatography coupled with light scattering, absorbance, and refractive index detectors.

Size-exclusion chromatography (SEC), coupled with "on-line" static laser light scattering (LS), refractive index (RI), and ultraviolet (UV) detection, provides a universal approach for determination of the molar mass and oligomeric state in solution of native proteins as well as glycosylated proteins or membrane proteins solubilized in non-ionic detergents. Such glycosylated proteins or protein-detergent complexes show anomalous behavior on SEC, thus presenting a challenge to determination of molar mass and oligomeric state in solution. In the SEC-UV/LS/RI approach, SEC serves solely as a fractionation step, while the responses from the three detectors are utilized to calculate the molar mass for the polypeptide portion of the native or modified protein. The amount of sugar, lipid, or detergent bound to the polypeptide chain can also be estimated from the SEC-UV/LS/RI analysis.

Calibration↗
PubMed2005

Characterization of oligomeric species in the fibrillization pathway of the yeast prion Ure2p.

The [URE3] prion of Saccharomyces cerevisiae shares many features with mammalian prions and poly-glutamine related disorders and has become a model for studying amyloid diseases. The development of the [URE3] phenotype is thought to be caused by a structural switch in the Ure2p protein. In [URE3] cells, Ure2p is found predominantly in an aggregated state, while it is a soluble dimer in wild-type cells. In vitro, Ure2p forms fibrils with amyloid-like properties. Several studies suggest that the N-terminal domain of Ure2p is essential for prion formation. In this work, we investigated the fibril formation of Ure2p by isolating soluble oligomeric species, which are generated during fibrillization, and characterized them with respect to size and structure. Our data support the critical role of the N-terminal domain for fibril formation, as we observed fibrils in the presence of 5 M guanidinium chloride, conditions at which the C-terminal domain is completely unfolded. Based on fluorescence measurements, we conclude that the structure of the C-terminal domain is very similar in dimeric and fibrillar Ure2p. When studying the time course of fibrillization, we detected the formation of small, soluble oligomeric species during the early stages of the process. Their remarkable resistance against denaturants, their increased content of beta-structure, and their ability to 'seed' Ure2p fibrillization suggest that conversion to the amyloid-like conformation has already occurred. Thus, they likely represent critical intermediates in the fibrillization pathway of Ure2p.

Chromatography, Gel↗
PubMed1980

Hemocyanins in spiders, IX. Homogeneity, subunit composition and the basic oligomeric structure of Eurypelma californicum hemocyanin.

37S hemocyanin isolated from the tarantula Eurypelma californicum was subjected to a variety of fractionation procedures: Electrophoresis in polyacrylamide gels, isoelectrofocusing, and ion exchange chromatography. Single fractions were dissociated at alkaline pH and/or by sodium dodecyl sulfate and the resulting subunits separated by polyacrylamide gel electrophoresis in gradient slab gels followed, in many cases, by quantitative estimation of the subunit bands. In addition, crossed immunoelectrophoresis was employed to analyze the subunit composition. Separation of the native hemocyanin into fractions with different subunit composition was not observed. Also, hemocyanin samples taken from individual spiders showed a strikingly uniform composition. It is concluded that Eurypelma hemocyanin is homogeneous for all practical means. This implies that the seven different polypeptide chains described previously for Eurypelma hemocyanin all take part in the formation of the 24 subunits, 37S oligomeric molecule. By monitoring chromatographic effluents at 280 nm, scanning stained electrophoresis gels and determining peak areas in these experiments and in crossed immunoelectrophoresis, the relative quantities of the seven different polypeptide chains in the whole molecule were determined as follows (number per 37S molecule): 6a, 2b, 2c2, 2c4, 4d, 4e, 4f. The ratio between a and c2 (6:2) is the least well established. Since 7 different polypeptide chains are incorporated, the hexameric molecule cannot represent the basic oligomeric structure in tarantula hemocyanin, but probably the dodekamer. If Eurypelma hemocyanin is incubated with sucrose, partial dissociation occurs, yielding a fragment sedimenting with ca. 28S. This process is reversible. The 28S fragment still contains all subunit species; it is thought to represent a (3 x 6) or closely related structure. The implications of this finding with respect to the symmetry of the native hemocyanin molecule are discussed.

Animals↗
PubMed2004

Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway.

Cytoplasmic deposition of alpha-synuclein aggregates is a common pathological feature of many neurodegenerative diseases. Strong evidence for the causative role of alpha-synuclein in these disorders is provided by genetic linkage between this gene and familial Parkinson's disease and by neurodegeneration in transgenic animals that overexpress this protein. In particular, it has been hypothesized that the accumulation of nonfibrillar oligomers of alpha-synuclein, which serve as intermediates for fibrillar inclusion body formation, causes neurodegeneration. However, little is known about how cells handle potentially toxic protein aggregates. Here we demonstrate that cells are capable of clearing preformed alpha-synuclein aggregates via the lysosomal degradation pathway. Consequently, blocking this pathway causes the accumulation of the aggregates in non-neuronal cells, differentiated neuroblastoma cells, and primary cortical neurons. This aggregate clearance occurs in an aggregation stage-specific manner; oligomeric intermediates are susceptible to clearance, whereas mature fibrillar inclusion bodies are not. Neutralization of the acidic compartments leads to the accumulation of alpha-synuclein aggregates and exacerbates alpha-synuclein toxicity in postmitotic neuronal cells, suggesting that the accumulation of oligomeric intermediates may be an important event leading to alpha-synuclein-mediated cell death. These results suggest that enhancing lysosomal function may be a potential therapeutic strategy to halt or even prevent the pathogenesis of Parkinson's disease and other Lewy body diseases.

Animals↗