Flavin dependent O2-activation: comments on the structure of "complexes" between reduced flavocoenzyme and molecular oxygen.
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Binding Sites↗
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Structural ambiguity and limits to coping.
How well a person can cope with any situation is determined, among other factors, by his ability to resolve the ambiguity of that situation, which in turn depends on its structural complexity. We attempted to analyze a whole range of situations in terms of three dimesions: differentiations, the number of alternatives perceived; articulation, the differentiation and rankability of these alternatives; and loading, the emotional loading (positive or negative) associated with the situation. The efficiency of mapping with these dimensions was investigated by analyzing the effects of 75 situations on coping, as reported in the literature. These were divided into three groups, 25 situations in each, associated with good coping, reduced coping, and failure to come (in terms of performance relative to a baseline or to the population's norm). The interaction between the demands imposed by the complexity of the situation and the success of coping was analyzed by the Multidimensional Scalogram Analysis (MSA). Results show effectiveness of coping to be inversely related to the structural complexity of a situation, mapped in terms of articulation, loading and differentiation. The relative importance of these dimensions is as ordered above; this offers a possible way to construct an "ambiguity score" which may be the primary factor determining the coping limit set by any situation.
Adaptation, Psychological↗
The bacterial flagella motor.
The bacterial flagellum is probably the most complex organelle found in bacteria. Although the ribosome may be made of slightly more subunits, the bacterial flagellum is a more organized and complex structure. The limited number of flagella must be targeted to the correct place on the cell membrane and a structure with cytoplasmic, cytoplasmic membrane, outer membrane and extracellular components must be assembled. The process of controlled transcription and assembly is still not fully understood. Once assembled, the motor complex in the cytoplasmic membrane rotates, driven by the transmembrane ion gradient, at speeds that can reach many 100 Hz, driving the bacterial cell at several body lengths a second. This coupling of an electrochemical gradient to mechanical rotational work is another fascinating feature of the bacterial motor. A significant percentage of a bacterium's energy may be used in synthesizing the complex structure of the flagellum and driving its rotation. Although patterns of swimming may be random in uniform environments, in the natural environment, where cells are confronted with gradients of metabolites and toxins, motility is used to move bacteria towards their optimum environment for growth and survival. A sensory system therefore controls the switching frequency of the rotating flagellum. This review deals primarily with the structure and operation of the bacterial flagellum. There has been a great deal of research in this area over the past 20 years and only some of this has been included. We apologize in advance if certain areas are covered rather thinly, but hope that interested readers will look at the excellent detailed reviews on those areas cited at those points.
Bacteria↗
Isolation of functional alpha beta heterodimers from the purified human placental alpha 2 beta 2 heterotetrameric insulin receptor complex. A structural basis for insulin binding heterogeneity.
To investigate the role of subunit communication in the insulin binding and tyrosine-specific protein kinase activities of the purified human placental insulin receptor, we have developed the methodology to isolate a functional alpha beta heterodimeric insulin receptor complex from the native alpha 2 beta 2 heterotetrameric disulfide-linked state. The dissociation of the alpha 2 beta 2 heterotetrameric insulin receptor into an alpha beta heterodimer was found to be approximately 50% efficient by treatment with alkaline pH (8.75) and dithiothreitol (2 mM). Removal of the dithiothreitol and pH neutralization (pH 7.60) by rapid Sephadex G-50 gel filtration resulted in the preservation of tracer insulin binding activity. The nondissociated alpha 2 beta 2 heterotetrameric and alpha beta heterodimeric insulin receptor complexes could then be effectively separated by Bio-Gel A-1.5m gel filtration. Scatchard analyses of insulin binding to the alpha 2 beta 2 heterotetrameric control or dithiothreitol-treated but nondissociated alpha 2 beta 2 heterotetrameric insulin receptor complexes demonstrated a curvilinear binding isotherm with a maximum of 1 mol of insulin bound/mol of alpha 2 beta 2 heterotetrameric complex. However, binding analyses performed on the isolated alpha beta heterodimeric complex yielded a nearly linear binding curve also, with 1 mol of insulin bound/mol of alpha beta heterodimeric complex at saturation. These data demonstrate that the insulin half-site binding reactivity observed in the alpha 2 beta 2 heterotetrameric insulin receptor complex results from either an asymmetric assembly of identical alpha beta heterodimers or from absolute negative cooperativity.
Chromatography, Gel↗
Chaotic behavior of hemodynamics with ventricular assist system.
In order to analyze hemodynamic parameters during left ventricular assistance as an entity and not as decomposed parts, non-linear mathematical techniques were utilized. Pneumatically actuated ventricular assist systems (VAS) were implanted as left heart bypasses in acute animal experiments, using healthy adult mongrel dogs. By the use of the non-linear mathematical technique, the arterial blood pressure waveform (AP) was embedded into the four-dimensional phase space and projected into the three-dimensional phase space. The Lyapunov numerical method was used as an adjunct to the graphical analysis of the state space. The phase portrait of the attractor showed a complex structure; a three dimensional solid torus with a screw type structure as a part, suggesting deterministic chaos in the AP without left ventricular assistance. Positive lyapunov exponents confirmed the existence of chaos. During counterpulsation mode left ventricular assistance, the phase portrait of the attractor showed a more complex structure, and positive Lyapunov exponents suggested a greater dimensional deterministic chaos. However, non-structured patterns were seen in the phase space during internal mode VAS driving, suggesting the possibility of dissipative dynamics in the four dimensional phase space. These results suggest that the cardiovascular system with counterpulsation mode VAS driving is in a homeochaotic state, which is thought to be a flexible and intelligent control system. And there is greater dimensional complex dynamics in the circulatory regulatory system with VAD during internal mode assistance.
Animals↗
Functional interactions between the proline-rich and repeat regions of tau enhance microtubule binding and assembly.
Tau is a neuronal microtubule-associated protein that promotes microtubule assembly, stability, and bundling in axons. Two distinct regions of tau are important for the tau-microtubule interaction, a relatively well-characterized "repeat region" in the carboxyl terminus (containing either three or four imperfect 18-amino acid repeats separated by 13- or 14-amino acid long inter-repeats) and a more centrally located, relatively poorly characterized proline-rich region. By using amino-terminal truncation analyses of tau, we have localized the microtubule binding activity of the proline-rich region to Lys215-Asn246 and identified a small sequence within this region, 215KKVAVVR221, that exerts a strong influence on microtubule binding and assembly in both three- and four-repeat tau isoforms. Site-directed mutagenesis experiments indicate that these capabilities are derived largely from Lys215/Lys216 and Arg221. In marked contrast to synthetic peptides corresponding to the repeat region, peptides corresponding to Lys215-Asn246 and Lys215-Thr222 alone possess little or no ability to promote microtubule assembly, and the peptide Lys215-Thr222 does not effectively suppress in vitro microtubule dynamics. However, combining the proline-rich region sequences (Lys215-Asn246) with their adjacent repeat region sequences within a single peptide (Lys215-Lys272) enhances microtubule assembly by 10-fold, suggesting intramolecular interactions between the proline-rich and repeat regions. Structural complexity in this region of tau also is suggested by sequential amino-terminal deletions through the proline-rich and repeat regions, which reveal an unusual pattern of loss and gain of function. Thus, these data lead to a model in which efficient microtubule binding and assembly activities by tau require intramolecular interactions between its repeat and proline-rich regions. This model, invoking structural complexity for the microtubule-bound conformation of tau, is fundamentally different from previous models of tau structure and function, which viewed tau as a simple linear array of independently acting tubulin-binding sites.
Amino Acid Sequence↗
[Lipoproteins as a specific circulatory transport system].
In accordance with the systemic approach, each circulatory transport system is highly specific and transports an elementary substance from cell to cell in the hydrated medium. In the author's opinion, the lipoprotein system has also a functional specificity and carries the elementary substance fatty acid in the blood stream. A great variety of fatty acids, the individuality of their physicochemical properties, great stereochemic differences of saturated and polyenic fatty acids make their transport virtually impossible. The steric individuality of fatty acids can be reduced if the acids are covalently bonded by a matrix as complex lipids. For formation of complex lipids, nature prefers esterification of fatty acids with alcohols which have a varying hydrophoby, such as glycerol, sphingosine, cholesterol, cetyl alcohol. The steric differences of saturated and polyenic fatty acids form a basis for their being structurized in different lipids. Triacyl glycerides are a transport form of saturated, monounsaturated fatty acids and their transforms and give rise to a crystalline phase. Phospholipids and cholesterol esters are a transport form of mainly polyunsaturated fatty acids in the polar phase in the former case and in the crystalline phase in the latter one. The individual apolipoproteins structure complex lipids into individual lipoprotein particles and transport them in the hydrated medium of blood flow. Saturated fatty acids chiefly transport lipoprotein particles formed by apoB-48- and apoB-100-isoproteins. Polyenic acids transport mainly high-density apoA-1-lipoprotein particles, which makes up a main physiological function of the latter. Cholesterol is nothing more than a matrix; it reesterifies polyenic fatty acids from the polar transport form of phospholipids into the unpolar transport form of cholesterol esters. Cholesterol esterification of polyenic fatty acids may structure complex lipid in the unpolar phase and transport it to the cells via apoB-100-ligand-receptor interaction, which is considered to be a key stage in the multistage process of active transport to the cells of polyenic fatty acids. However, the significant differences of active and inactive transport of polyenic fatty acids in the blood stream await a separate consideration.
Biological Transport, Active↗
X-ray structure of ornithine decarboxylase from Trypanosoma brucei: the native structure and the structure in complex with alpha-difluoromethylornithine.
Ornithine decarboxylase (ODC) is a pyridoxal 5'-phosphate (PLP) dependent homodimeric enzyme. It is a recognized drug target against African sleeping sickness, caused by Trypanosoma brucei. One of the currently used drugs, alpha-difluoromethylornithine (DFMO), is a suicide inhibitor of ODC. The structure of the T. brucei ODC (TbODC) mutant K69A bound to DFMO has been determined by X-ray crystallography to 2.0 A resolution. The protein crystallizes in the space group P2(1) (a = 66.8 A, b = 154.5 A, c = 77.1 A, beta = 90.58 degrees ), with two dimers per asymmetric unit. The initial phasing was done by molecular replacement with the mouse ODC structure. The structure of wild-type uncomplexed TbODC was also determined to 2.9 A resolution by molecular replacement using the TbODC DFMO-bound structure as the search model. The N-terminal domain of ODC is a beta/alpha-barrel, and the C-terminal domain of ODC is a modified Greek key beta-barrel. In comparison to structurally related alanine racemase, the two domains are rotated 27 degrees relative to each other. In addition, two of the beta-strands in the C-terminal domain have exchanged positions in order to maintain the location of essential active site residues in the context of the domain rotation. In ODC, the contacts in the dimer interface are formed primarily by the C-terminal domains, which interact through six aromatic rings that form stacking interactions across the domain boundary. The PLP binding site is formed by the C-termini of beta-strands and loops in the beta/alpha-barrel. In the native structure Lys69 forms a Schiff base with PLP. In both structures, the phosphate of PLP is bound between the seventh and eighth strands forming interactions with Arg277 and a Gly loop (residues 235-237). The pyridine nitrogen of PLP interacts with Glu274. DFMO forms a Schiff base with PLP and is covalently attached to Cys360. It is bound at the dimer interface and the delta-carbon amino group of DFMO is positioned between Asp361 of one subunit and Asp332 of the other. In comparison to the wild-type uncomplexed structure, Cys-360 has rotated 145 degrees toward the active site in the DFMO-bound structure. No domain, subunit rotations, or other significant structural changes are observed upon ligand binding. The structure offers insight into the enzyme mechanism by providing details of the enzyme/inhibitor binding site and allows for a detailed comparison between the enzymes from the host and parasite which will aid in selective inhibitor design.
Amino Acid Sequence↗
Fate of gap junctions in isolated adult mammalian cardiomyocytes.
The fate of gap junctions in dissociated adult myocytes, maintained for up to 22 hours in culture medium, was investigated by semiquantitative analysis of thin sections and by freeze-fracture electron microscopy. Gap junctions in the dissociated myocyte are intact bimembranous structures seen either as invaginated surface-located structures or as annular profiles in the cytoplasm. Surface-located junctions are sealed from the exterior by a sheet of nonjunctional membrane originating (together with the "outer" junctional membrane) from the formerly neighboring cell. Serial sectioning was used to establish that at least part of the annular gap junction population in the freshly isolated myocyte represents truly discrete cytoplasmic vesicles; thus, some gap junctions are rapidly endocytosed after myocyte separation. Analysis of the surface-located-to-annular gap junction ratio suggested that no further endocytosis occurred in rabbit and cat myocytes maintained for 22 and 15 hours, respectively. Guinea pig myocytes, by contrast, did appear to continue endocytosis in culture. Analysis of the distance of gap junctional structures from the cell surface suggested that little if any inward migration of gap junction vesicles occurred. Hypoxia had no detectable effect on the internalization or inward movement of gap junctions. The quantity of ultrastructurally detectable gap junction membrane appeared to remain constant over time, as did the incidence of "complex structures" (i.e., annular gap junction profiles with features previously suggested to represent degradation). New gap junction formation was negligible, and a reappraisal of the nature of "complex structures" led to the conclusion that the origin of these structures need not be related to degradation. Taken together, the findings suggest that degradation and disappearance of gap junctional membrane after isolation of the mature myocyte constitute a much slower process than previously believed, and the possibility that the cardiac gap junction protein has a longer half-life than its counterpart in liver remains open.
Animals↗
Conformational alteration in foot-and-mouth disease virus virion capsid structure after complexing with monospecific antibody.
A mechanism of neutralization of virus infectivity by antibody is described and related to the immune defences in vivo. The interaction of a particular monoclonal antibody with homologous foot-and-mouth disease virus alters the conformation of the virions to permit penetration of staining reagents. A consequence of this structural alteration is that the RNA genome becomes susceptible to dissociation from the capsid proteins. This mechanism of virus neutralization is irreversible and therefore provides an effective in vivo defence measure against virus attack, complementing the enhanced phagocytosis effected through opsonization of virions. With viruses that can replicate in phagocytes, such a mechanism of virus neutralization could provide a major 'specific' immunological defence against virus invasion.
Antibodies, Monoclonal↗
Prediction of the three-dimensional structures of complexes of lysozyme with cell wall substrates.
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Acetylglucosamine↗
Analysis of the mechanical behavior of the Nijdam voice prosthesis.
The valveless Nijdam prosthesis is a new voice prosthesis for laryngectomized patients using tracheoesophageal speech. An "umbrella-like hat" covers the esophageal side of the tracheoesophageal fistula and is deformed during speech by air pressure. To decrease pressure loss during speech, a good understanding of the mechanical behavior is essential. In the present study, the Finite Element Method (FEM), used in engineering to analyze the mechanical behavior of complex structures, was applied to analyze eight possible improvements of the Nijdam prosthesis. This study found that, during speech, deformation of hat and soft tissue occur. Distinct differences in the hat's deformation of the eight models also were found. It is concluded that complex structures like the Nijdam prosthesis can be analyzed by FEM. An optimal model was found to decrease pressure loss while stresses in the device remain safe.
Equipment Design↗
Synthesis and antitumor activity of the metformin platinum (IV) complex. Crystal structure of the tetrachloro(metformin)platinum (IV) dimethylsulfoxide solvate.
The synthesis of (metformin) tetrachloroplatinum (IV) was investigated (metformin is N,N-dimethylbiguanide). It crystallizes with one dimethylsulfoxide molecule as solvate in the monoclinic system, space group P2(1)/n (No. 14) with Z = 4. The cell dimensions are: a = 13.136(7), b = 9.424(2), c = 14.009(8) A, beta = 111.96(4) degrees, V = 1608.4(2) A3. Of the 4269 independent nonzero reflections collected, 1979 with I > 3 sigma (I) were considered and used in the calculations. The structure was refined to R = 0.043 and wR = 0.045. The platinum coordination is octahedral, built up from four chloride anions and one bidentate chelating ligand via the two imine nitrogen atoms cis position. The distances and angles are typical of six-membered rings that have similar donor atoms. The complex was evaluated in vitro and in vivo on murine P388 leukemia. It was found to be as potent as cis-dichlorodiammine platinum (II), CDDP, in inhibiting the proliferation of the sensitive P388 cells. However the resistant P388/CDDP cells were threefold more sensitive to the compound than to CDDP. The two compounds induced a similar perturbation in the G2+M phases of the cell-cycle. The complex was less active than CDDP in vivo on P388 leukemia when administered i.p. (intra peritoneal) on day 1.
Animals↗
A new stacking motif: complex alloy structures interpreted as modulated structures.
The structures of lambda-Al4Mn, manganese aluminide, kappa-Al177Cr49Ni, chromium nickel aluminide, and epsilon-Al4Cr, chromium aluminide, which have been described in terms of the aggregation of clusters until now, are interpreted as modulated structures. They are basically composed of close-packed layers with ordered atomic vacancies. The observed stacking motif of the atoms can be found in many phases related to icosahedral and decagonal quasicrystals. This analysis will be helpful in the study of not only many complex alloys, but also quasicrystals.
Alloys↗
The complexity of structures involved in T-cell activation.
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Animals↗
Human leucocyte aspartylglucosaminidase. Evidence for two different subunits in a more complex native structure.
Human leucocyte aspartylglucosaminidase (AGA: 1-aspartamido-beta-N-acetylglucosamine amidohydrolase, EC 3.5.1.26) was purified to homogeneity by using affinity chromatography, gel filtration, chromatofocusing and reverse-phase h.p.l.c. As shown by SDS/PAGE, the homogeneous purified enzyme preparation consists of four polypeptide chains with molecular masses of 25, 24, 18 and 17 kDa. In the native polyacrylamide gel these polypeptides migrate as one active enzyme complex, and by gel filtration the peak of enzyme activity can be detected in a position of about 65 kDa. Digestion with endoproteinase Lys-C or endoproteinase Asp-N, followed by peptide analysis with reverse-phase h.p.l.c., reveals an identical peptide pattern for the 24 and 25 kDa bands as well as for the 17 and 18 kDa bands. This treatment further demonstrated a totally different peptide pattern for the 24/25 kDa versus the 17/18 kDa subunit. The N-terminal sequences of the 17 kDa and the 18 kDa peptides were identical, as determined by Edman degradation. The N-termini of the 24 kDa and the 25 kDa peptides were blocked. The enzyme was partly resistant to endoglycosidases H and F, but N-glycosidase F transformed the 24/25 kDa band into one 23 kDa band and the 17/18 kDa band into one 16 kDa band. Also, immunological data obtained with antisera produced against these subunits showed that AGA consists of two non-identical polypeptides.
Amino Acid Sequence↗
Formation and maturation of the calcium release apparatus in developing and adult avian myocardium.
Muscle fibers release large amounts of calcium from an internal compartment, the sarcoplasmic reticulum (SR), during activation. Two proteins are involved in this process and its control: plasma membrane calcium channels, or dihydropyridine receptors (DHPRs), and SR calcium release channels, or ryanodine receptors (RyRs). The two proteins form part of a structural complex, perhaps unique to muscle cells, which allows an interaction between plasma membrane and SR, resulting in calcium release from the latter. The surface-SR interaction is a step in the coupling between electrical events in the plasma membrane and contraction (excitation-contraction coupling). The structural complexes have been called calcium release units. One key to further understanding the control of calcium homeostasis in muscle is knowledge of how DHPRs and RyRs assemble into calcium release units. We have studied the development of avian myocardium, using immunocytochemistry to locate DHPRs and RyRs and electron microscopy to follow the formation of calcium release units containing feet (RyRs) and large membrane particles (presumably DHPRs). We find that the initial step is a docking of SR vesicles to the plasma membrane, followed by the appearance of feet in the junctional gap between SR and plasma membrane. Feet aggregate in ordered arrays, and the arrays increase in size until they fill the entire junctional gap. Clustering of membrane particles, presumably DHPRs, is apparently coupled to clustering of feet, since the two junction components assemble within patches of membrane of approximately equal size and containing an approximately constant ratio of particles to feet. Thus, despite the fact that no evidence exists for a direct interaction between DHPRs and RyRs in cardiac muscle, some mechanism exists to ensure that the two molecules are clustered in proximity to each other and in the appropriate proportion.
Animals↗
A complex nucleoprotein structure involved in activation of transcription of two divergent Escherichia coli promoters.
Initiation of transcription at malEp and malKp, two divergent Escherichia coli promoters, depends on the presence of both CRP, a pleiotropic activator, and MalT, the maltose regulon activator. We carried out in vivo genetic and functional analysis of these promoters and characterized their interaction with MalT and CRP using DNase I footprinting. The functional limits of the promoters are located about 240 base-pairs (bp) upstream of their transcription start sites, which are 271 bp apart. These promoters therefore overlap by about 210 bp. The overlapping region encompasses four CRP-binding sites and at least four MalT-binding sites. Insertions in the centre of this region are tolerated provided that they correspond to an integral number of DNA helix turns. In DNase I footprinting experiments performed on the complex formed by MalT with malEp-malKp, the DNA appears to be wrapped around the protein. We propose a model for the nucleoprotein structure that might be involved in transcription activation at these divergent promoters.
Bacterial Proteins↗