In the genome of a germ-line cell, the genetic information for an immunoglobulin polypeptide chain is contained in multiple gene segments scattered along a chromosome. During the development of bone marrow-derived lymphocytes, these gene segments are assembled by recombination which leads to the formation of a complete gene. In addition, mutations are somatically introduced at a high rate into the amino-terminal region. Both somatic recombination and mutation contribute greatly to an increase in the diversity of antibody synthesized by a single organism.

Somatic generation of antibody diversity

The class I histocompatibility antigen from human cell membranes has two structural motifs: the membrane-proximal end of the glycoprotein contains two domains with immunoglobulin-folds that are paired in a novel manner, and the region distal from the membrane is a platform of eight antiparallel beta-strands topped by alpha-helices. A large groove between the alpha-helices provides a binding site for processed foreign antigens. An unknown 'antigen' is found in this site in crystals of purified HLA-A2.

Structure of the human class I histocompatibility antigen, HLA-A2.

The four distinct T-cell antigen receptor polypeptides (alpha, beta, gamma, delta) form two different heterodimers (alpha:beta and gamma:delta) that are very similar to immunoglobulins in primary sequence, gene organization and modes of rearrangement. Whereas antibodies have both soluble and membrane forms that can bind to antigens alone, T-cell receptors exist only on cell surfaces and recognize antigen fragments only when they are embedded in major histocompatibility complex (MHC) molecules. Patterns of diversity in T-cell receptor genes together with structural features of immunoglobulin and MHC molecules suggest a model for how this recognition might occur. This view of T-cell recognition has implications for how the receptors might be selected in the thymus and how they (and immunoglobulins) may have arisen during evolution.

T-cell antigen receptor genes and T-cell recognition.

Glycobiology: Toward Understanding the Function of Sugars.

Canonical structures for the hypervariable regions of immunoglobulins

Publisher Summary This chapter discusses a study analyzing the three-dimensional structure of immunoglobulins. Heavy atom derivatives were obtained. The compounds used were (1) p -chloromercuribenzene sulfonate (PCMBS), (2) mercuric cyanide Hg(CN) 2 , and (3) chloroplatinate ion, (PtCl 6 −− ). X-ray diffraction data were measured for the native crystals and each of the heavy atom derivatives to a Bragg spacing of 6 A. Electron micrographs were prepared of sections of the Dob crystals, cut perpendicular to the short c axis. The crystals were fixed with glutaraldehyde, washed, postfixed in osmium tetroxide, and embedded in Maraglas prior to sectioning. The sections were further stained with uranyl acetate and lead citrate solutions. The method of optical integration was applied in which the periodicity of the crystal was used to reduce the background noise and reveal the molecular outline. An electron density map was calculated with phases obtained from the heavy atom derivatives. The examination of the map showed that one pair of asymmetric units (containing one complete molecule) had density corresponding to three globular regions. One region lay on the twofold axis relating the two halves of the Dob molecule.

L M Amzel

Papers

Three-Dimensional Structure of Immunoglobulins