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The complete amino acid sequence of the heavy chain variable regions of two different molecules of immunoglobulin M anti-gamma globulin has been determined. These proteins, from different human patients, had independently been shown to share idiotypic specificity. Only eight sequence differences were discernible for the entire length of their heavy chain variable regions. Five of the differences occurred outside hypervariable regions, while three were placeable within such regions. A comparison of these molecules of anti-gamma globulin with the seven human VHIII variable region sequences presently available for immunoglobulins without known antibody activity showed that the great majority of sequence differences between the two idiotypically similar antibodies and these seven proteins were confined to hypervariable regions.This study illustrates in precise terms a convergence of the distinct immunological properties of idiotypy, hypervariable region structure, and combining site specificity as they relate to the variable region of the immunoglobulin molecule. To a great degree these properties now appear to be a reflection of the same structural attributes of the variable region.

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The variable regions of five human immunoglobulin heavy chains of the VHIII subgroup have been totally sequenced. Three of the heavy chains belonged to the IgG class and two to the IgA class. Examination of these sequences, and comparison with additional published heavy chain sequences, showed that a total offour hypervariable regions is characteristic of human heavy chain variable regions.The relatively conserved character of large segments of the heavy chain variable region was very evident in these studies. The conserved segments, which are those sections located outside the hypervariable regions, comprise approximately 65% of the total heavy chain variable region. The following general structural pattern for antibody molecules emerges from this and related studies: an overall combining region superstructure is provided by the more conserved segments while the refinements of the active site specificity are a function of hypervariable regions.The antibody combining site is now believed to reside exclusively in the variable regions of the heavy and light polypeptide chains of the immunoglobulin molecule. Evidence is accumulating from several laboratories which indicates that hypervariable regions within the variable region are directly involved in the antibody combining site as well as being responsible, at least in part, for the idiotypic determinants of myeloma proteins and specific antibodies (1-5).The existence of three hypervariable regions in the variable region of human immunoglobulin heavy chains has been established by previous studies from this laboratory. Residues 31-37 were described as the first hypervariable region of the heavy chain (6), and, after fragmentation of IgG heavy chains with cyanogen bromide, two additional hypervariable regions were localized between residues 86-91 and 101-110 (7).We have now completed the amino acid sequence from residues 41 to 84 of the three VHIII proteins originally reported (6, 7)