Hinge-regIon deletion localized in the IgG1-globulin Mcg

Fett, James W.; Deutsch, H.F.; Smithies, O.

doi:10.1016/0019-2791(73)90238-3

Cited by 79 publications

(21 citation statements)

References 13 publications

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“…Symbols see Fig. 1 crystalline antibodies [22,23] a deletion in the hinge region has been found [24,25]. We think that an intact hinge region plays an important role in the flexibility of the whole molecule [9,26] and this could therefore have an influence on the overall dimensions of the molecule.…”

Section: Discussionmentioning

confidence: 99%

Small-Angle X-Ray Studies of the Human Immunoglobulin Molecule Kol

1977

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The conformation of the human immunoglobulin molecule Kol [IgG I, xz yz, Gm(f)+] was studied by small-angle X-ray scattering in 0.15 M NaCl solution. The radius of gyration was found to be 5.84 k 0.04 nm, the volume 329 k 15 nm3 and the molecular weight 150000 k 10000.Information on the overall shape was obtained by comparing the experimental scattering curve with the calculated curves for various models. The models were obtained by arranging the models found for the Fab and Fc fragments of the same immunoglobulin molecule in a different manner. A model which fits all the date and the form of the experimental scattering curve is presented.In .recent years the overall structure of various immunoglobulins [l, 21 and their change upon interaction with antigen [3,4] have been studied in solution by small-angle X-ray scattering. The shape of the immunoglobulin G (IgG) molecule was simply approximated by a model composed of a few triaxial bodies. The single fragments Fab and Fc were described by one triaxial body.With the human immunoglobulin molecule Kol and its fragments Fab and Fc we looked for more detailed models which fit the small-angle data better. The investigations on the fragments and detailed models for their structure in solution have been published recently [5]. In this paper the results obtained for the whole IgG molecule Kol are presented. EXPERIMENTAL PROCEDURE Muter iulsThe immunoglobulin molecule Kol has been isolated from the serum of a female patient suffering from multiple myeloma. The methods for its isolation and purification and physicochemical characterisation have been published in detail elsewhere [6,7] and will be mentioned here only briefly.The protein, which is a cryoprotein, was collected by centrifugation of the serum in the cold. The precipitate was washed several times and finally dissolved in the buffer system which was used for the purification of the protein in ion-exchange chromatography. The homogeneity of the isolated protein was shown by electrophoretic and immunoelectrophoretic methods and by serological typing and analytical ultracentrifugation.Finally the protein was crystallised [6,7]; the crystals are suitable for X-ray crystallographic measurements at high resolution [8,9]. Smu 11-Angle X -Ray ScatteringA stabilized high-power X-ray generator (Philips PW 1140) with a tube with copper target delivered a sufficiently high primary intensity (50 kV and 30 mA). A Kratky camera with slit collimation [lo] was used. The scattered intensities were measured at an angle range of 0.00215-0.1 rad using an 120-pm entrance slit.For recording, a proportional counter with an X-ray analysis channel control and measuring system of Philips were used. The pulse height discriminator was focused on the Cu Ka line (0.154 nm). The elimination of the Cu KP line (0.139 nm) was effected by a mathematical procedure using a computer program [l 1 1. A programmable electronic step-scanning device [12] allowed a fully automatized operation which also includes the possibility of a repeated scanning of ...

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Section: Discussionmentioning

confidence: 99%

Small-Angle X-Ray Studies of the Human Immunoglobulin Molecule Kol

1977

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“…Three such proteins have been described: IgGLK Dob (7), IgGiK Lec (8), and IgGlA McG (9). The structural defect in these molecules is identical and involves a deletion of residues [216][217][218][219][220][221][222][223][224][225][226][227][228][229][230] of the normal yl sequence, which corresponds to the entire hinge region.…”

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confidence: 99%

Expression of biological effector functions by immunoglobulin G molecules lacking the hinge region.

Klein¹,

Haeffner‐Cavaillon²,

Isenman³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

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Several biological effector functions mediated by sites on the Fc region of human IgG1 have been studied in two variant IgGlK monoclonal proteins (Dob and Lec) which contain deletions corresponding to the entire hinge region of the heavy chains. Neither Dob nor Lec protein in aggregated form was able to activate the classical complement pathway, and this was shown to be due to an inability to bind the first component of complement (Cl). By rosette inhibition assays, Dob and Lec proteins were shown to have no measurable affinity for Fc receptors on human B cells or neutrophils. Dob and Lec proteins had a much reduced affinity for Fc receptors on the murine macrophage-like cell line P388D1 when compared to normal human IgGi. Furthermore, the hinge-deleted proteins were able to compete with murine IgG2b for P388D, receptors but not with murine IgG2a. In contrast, the binding of Dob and Lec proteins to protein A from Staphylococcus aureus was entirely normal. The functional consequences of the hinge deletion were parallel to those seen when normal IgGI was reduced and alkylated. It was concluded that the functional impotency of Dob and Lec proteins was related to the close association between the Fab and Fc regions in these molecules and the limited degree of segmental flexibility permitted in the absence of the hinge region. The data also suggest a major role for the C'y2 domain (C is the constant region) in mediating effector functions in normal IgGl.

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“…In y-HCD with an homogeneous Nterminal sequence, the protein starts at the amino-terminal sequence of the VKpart followed by a partial deletion of In protein HAL [ 121, the deletion is longer, including the hinge region and the beginning of the C H~ domain. Finally, an IgG, protein [42] has been studied showing a deletion of the hinge region, with a normal Fd fragment. The immunochem.…”

Section: Resultsmentioning

confidence: 99%

Immunochemical and biochemical study of a human Fcμ fragment (μ‐chain disease)

et al. 1975

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An abnormal protein, from a petient with mu-chain disease has been studied: protein BUR. It is devoid of the F (ab'')2 mu fragment; molecular weight determinations and immunological data identify the protein as a F(c) 5 mu fragment. Similarly, carbohydrate determinations and proteolysis experiments relate it to a Fcmu fragment. Nevertheless, the protein, which tontains J-chain, lacks the entire covalently bonded structure of the F (c)5mu fragment. C-terminal analysis shows a tyrosine residue identical to the C-terminal amino acid of mu-chains. Sequence of the N-terminal region determined for 15 residues shows identity with sequence 338-352 and sequence 333-347 of two entire mu-chains previously studied. The relation of BUR to other heavy chain disease proteins is discussed.

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Hinge-regIon deletion localized in the IgG1-globulin Mcg

Cited by 79 publications

References 13 publications

Small-Angle X-Ray Studies of the Human Immunoglobulin Molecule Kol

Small-Angle X-Ray Studies of the Human Immunoglobulin Molecule Kol

Expression of biological effector functions by immunoglobulin G molecules lacking the hinge region.

Immunochemical and biochemical study of a human Fcμ fragment (μ‐chain disease)

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