Molecular symmetry in the fibrinogen of the horse-donkey hybrid

Fibrinogen has a covalently dimeric structure as the molecule is composed of two sets of three non-identical, disulfide-linked peptide chains. In individuals, heterozygous for a genetic variant the two types of peptide chains, e.g. X and Y, are present in similar amounts. If the peptide chains combined at random during biosynthesis it is expected that one quarter of the molecules would be of the XX type, one quarter of the YY type and one half of the XY type. However, in 7 cases with genetically abnoraml variants, only symmetrical molecules were detected. As a model for heterozygous individuals, the hybrid between horse and donkey, i.e. mule or hinny, was studied. It is known that horse and donkey fibrinopeptides A differ in 4 amino acid residues and that mule peptide A is a mixture of horse and donkey peptides. Horse, donkey and hinny fibrinogen were cleaved with cyanogen bromide, the N-terminal disulfide knot purified, digested with endo Lys-C and fragments isolated by reversed-phase high-performance liquid chromatography. All components were identified by sequence analysis. The digests contain a covalently dimeric fragment from the N-terminal part of the Act chain as the enzyme cleaves after the lysine residue which follows in sequence the cystine residue connecting the two halves of the molecule. In the digest from hinny fibrinogen, two adjacent Chromatographie components were analysed. One of them was found to contain exclusively the horse sequence and the other exclusively the donkey sequence. The result proves that at least the Aa chains will not combine at random, but will selectively combine to produce symmetrical molecules. The underlying biosynthetic mechanism has not yet been identified, but may be related to allelic exclusion, micro-compartmentalization or incompatibility during peptide chain assembly.