considered as the 'signature' of the immunoglobulin fold.

The loops connecting the (3 strands are relatively short and, as a result, a majority of the residues of the domain are contained in the two (3 sheets. The strands exposed to solvent display the characteristic pattern of alternating polar-apolar residues, with the apolar side-chains extending towards the interior of the domain to form a hydrophobic core between the two 3 sheets. Most of the conserved residues in V and C domains of antibodies are found in this internal core, in particular two highly conserved cysteine residues which form an intramolecular disulfide bridge linking the two 3 sheets. Other core positions show extensive amino acid substitutions, but preserve the secondary and tertiary structures and, to a lesser extent, the hydrophobic character of the protein interior. At the two extremities of the domain structure, the 3 strands are connected by peptide loops of varying length and character. These connecting segments may form regular reverse turns or short a-helical stretches, but in most cases present an irregular structure.

Domain association

The Ig domains of antibodies are associated in pairs stabilized by noncovalent interactions. With the exception of the CH2 domains, Ig subunits interact over a large contact area and are tightly associated.

The variable domains associate to form VH—V, heterodimers in Fab fragments, or V,-VL homo-dimers in Bence Jones proteins, by face-to-face packing of the five-stranded 3 sheets. Two V domains are related by an approximate (heterodimer) or exact (homodimer) twofold axis of symmetry. Inter-sub-unit interactions are very extensive, with roughly 20% of the entire molecular surface of each domain buried upon dimerization. Highly conserved amino acid residues at the V||—VL interface allow the association of different pairs of light and heavy chains to form the antibody molecule.

The constant domains of antibodies and Bence Jones proteins also form closely packed dimers. As in V dimers, paired C domains are related by an approximate (CH1-Ci.) or exact (Q-C,., Cn3-CH3i twofold axis of symmetry, and the arrangement of subunits among all the C-type pairs studied is very-similar. There is, however, a reversal of domain-domain interactions compared to V dimers: C dimers are formed by a close packing of the four-stranded 3 sheets which in V domains are exposed to solvent.

The antigen-recognition site of the antibody molecule involves the hypervariable loops which connect the 3 strands at the distal extremity of the VM-V[ dimcr. Functional differentiation of variable domains is accomplished through extensive genetic restructuring of this region (amino acid insertions, deletions and substitutions), which confers the antibody mol ecule with a potentially unlimited range of antigen binding specificities without significantly affecting the basic structural framework of the Ig domains.

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