Comparison of invariant residues in the variable and constant regions of human K, human L, and mouse K Bence-Jones proteins.

Abstract

Studies of the tryptic peptides by fingerprintinigl-4 and determination of the sequences of human K, human ]L, and mouse K Bence-Jones proteins5'have established that each of these three groups of proteins is made up of a variable and a constant region, comprising approximately the amino-terminal and carboxy-terminal halves of the molecules, respectively. In the variable region individual BenceJones proteins of each group may have different amino acid substitutions at a given position in the sequence, while in the constant region all proteins of each group have the same sequence except for position 191 in human K proteins, which is associated with Inv specificity.8' 16 With sequences arranged to give maximum homology, a comparison of these two regions in the various proteins showed that the variable region has very few speciesspecific residues, e.g., residues in which the human K and L proteins differed from the mouse K, while many such differences were present in the constant region;17 with the publicationof the complete sequence of a type L Bence-Jones protein,'5 these values are now at most 2 to 4 as compared with 36 species-specific residues, respectively. From this it was hypothesized that the variable region tended to be preserved during evolution perhaps because of its importance for antibody combiiiing sites (cf. ref. 18), while the constanit region, being less critical, had conlsiderable freedom to mutate during evolutioni without seriously inifluencing the variable por'tioin. A further implicationi of this hypothesis would be that the invarianlt sequences of the two regions differed in composition and structure and that the variable regions of the three groups of Bence-Jones proteins might have a unique composition. A compilation of the available sequence data on the human K, mouse K, and human L proteins5-'5 shows that 26 residues are invariant (e.g., the same amino acid occurs at the same position in the sequence) in the variable region (two uncertain because of amide groups) as compared with 33 in the constant region of all proteins studied. An identica]L amino acid is found at an additional 10 and 29 positions in the variable and constant portions, respectively, of all human K and mouse K and at 6 and 9 more positions in the respective regions of humanl L and mouse K proteins. The compositions are given in Table 1. The amino acids making up the invariant residues in the human K and L anld mouse K proteins differ to an extraordinary degree in the two halves of the chains. The variable region contains six glycines and no alanine, valine, leucine, or histidine, while the constant region has no glycine, three alanines, three valines, three leucines, and two histidines. There are, however, two invariant isoleucines and one invariant arginine in the variable but none in the constant region. On the other hanid, the variable region has but two serines while the constaint region has five.