The temperature-dependence of domain interactions in the Fab, Fc, Fb and Fv fragments from human myeloma immunoglobulins (IgG) samples was investigated by scanning microcalorimetry, NMR and difference spectroscopy. The fragments were found to be very sensitive to temperature changes. Lowering the temperature below the physiological value (37 degrees C) considerably decreases the energy of interaction of the variable VH and VL domains, resulting at times in their dissociation. Since the association energies of VH and VL pairs can be affected by the result of somatic recombination and mutation events affecting antibody genes, immunoglobulins can fortuitously acquire the properties of cryoglobulins or cold autoantibodies and induce severe pathological states. It is postulated that this property of immunoglobulins, and by extension, of T-cell antigen receptors might have been one of the causes for the possible natural selection of homoiothermal animals. In these, the high conformational sensitivity of immunoglobulins to temperature change may be important in the mechanisms of induction of secondary functions in immune responses.

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An electron microscopy study of human myeloma IgG3 Kuc has shown that the hinge region in an intact molecule is in a compact state. The subunits are not fixed rigidly and are very mobile. These data are supported by results of ultracentrifugation and microcalorimetry.Non-extremal denaturating effects (pH 4.0, 20°C or pH 7.8, 65°C) lead to 'unfolding' of the hinge region which has a rod-like shape in electron micrographs.The interest shown in the structure of various human IgG subclasses is connected with the fact that the character of immune response is largely determined by the subclass affiliation of the IgG. The use of myeloma (monoclonal) IgG allows one to deal with a homogeneous population of molecules of a particular subclass.Human IgG subclasses are known to differ markedly in their biological and physico-chemical properties [I]. At the same time X-ray crystallographic studies [2 -81 have revealed that the Fab and Fc subunits of different IgG molecules are, as a whole, identical in structure. The main structural distinctions in the IgG molecule are associated with the hinge region [9], connecting the Fab and Fc subunits. The structure of the hinge region is known to influence the subunit mobility in the IgG molecule, and this affects its general conformation [6,7, 101. Many biological functions associated with the Fc subunit (binding to Clq, Fc receptors, etc.) are displayed practically in the same way for the isolated Fc subunits of different IgG subclasses, whereas these functions within the intact molecule may be not displayed or can differ quantitatively for different IgG subclasses. In the given case, we are dealing with the regulation of biological functions at the level of the whole molecule and hence the interest in structural studies of intact IgG is understandable. Crystallographic investigations of the intact molecules did not yield any promising results [l, 111, except for two cases of IgG with deletions of the hinge region [3, 81 and two cryoglobulins. This is a consequence of the subunit mobility even in crystals. Colman et al.[ll] performed a detailed investigation of IgGl Kol, and found that the Fc subunit is not localized in electron density maps. The authors explained this phenomenon by the high mobility of the Fc subunit relative to Fab. The existence of such a mobility seems to be a characteristic feature of most IgG. The available data on the structure of the intact IgG molecules are based mainly on the results of small-angle X-ray scattering We have demonstrated previously the potential of electron inicroscopy to obtain new information on IgG structure using myeloma IgGl 281. IgG3 significantly differs from the other IgG subclasses in its biological and physico-chemical properties. It has a longer hinge region, does not bind to staphylococcal protein A but, at the same time, actively binds to Clq. The literature data on the IgG3 structure are contradictory (see e.g. [15,29, 301) and the aim of the present work was to carry out a comprehensive analysis of myeloma IgG3 Kuc by el...

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Facies zonation of the Paleozoic basement of West Siberian geosyncline and its surroundings is presented. Facies megazones are distinguished according to types of sedimentation. Analysis of lateral and successive sedimentary sequences shows that the available data are insufficient to map the facies distribution over the whole territory of the geosyncline for short time slices. Only the Late Devonian section is supported by data sufficient for the proposed facies zonation. Five megazones, I, II, III, IV, and V, are distinguished in the westward direction. First three megazones make up a single lateral facies succession and represent sedimentary environments on and around the Siberian continent. Megazone IV includes shallow-water volcanic and sedimentary rocks that compose the Kazakhstan continent bounded by Early and Middle Carboniferous sutures in the west and east. Megazone V comprises fold-thrust (island arc) complexes of the eastern Urals. The main events in the geologic history of the region were associated with the interaction of two major crustal masses (Siberian and East European continents) and the young Kazakhstan continent in the oceanic space called the Paleoasian ocean. Only few fragments of this space occur in the present-day framework of the territory, the greatest part being sunk in subduction zones, especially in the large zone of the Main Uralian Fault. Production and accumulation of organic matter in pre-Mesozoic deposits occurred on continental shelves, which are most promising for Precambrian and Paleozoic oil and gas.

Intact Bence-Jones proteins TIM and LUS under simulated physiological conditions (10 mM phosphate buffer, pH 7.0, 100 mM NaCl, 37°C) did not display amyloidogenic properties. However, their isolated variable domains exhibit these qualities in full measure. Therefore, both intact proteins and their variable domains were studied using a complex of physical methods (scanning microcalorimetry, analytical centrifugation, optics) that allowed us to assess the stability of their tertiary and quaternary structures. The experimentally obtained thermodynamic functions indicated that the stability of isolated variable domains of TIM and LUS was comparable to the stability of similar domains in amyloidogenic proteins described earlier. However, inside the whole protein their stability was comparable to the stability of VL domains of ordinary Bence-Jones proteins. The decreased stability of the isolated variable domains of TIM and LUS was shown to be due both to weak interactions between a pair of variable domains (trans-interaction) and to a natural lack of interaction with the constant domains (cis-interaction).

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