Introns and higher-order structure in the evolution of serpins

Summary The serpins are a large family of eukaryotic proteins, many but not all of whose members are proteinase inhibitors. Most members of this family show relatively low sequence identity, but crystal structures determined for 6 different serpins are closely similar. The intron positions of 11 serpins, and the intron sizes in 9 of these 11, have been determined. There is considerable diversity in number, position, and size of introns among these serpins, though subsets show clear similarity or identity. Dendrograms derived from comparisons of DNA and amino acid sequences and of intron positions for the 11 serpins differ from each other and from dendrograms previously derived from protein sequences. These dendrograms are difficult to reconcile exclusively with a loss of introns from a large primordial set during the evolution of the serpin family. The tertiary structure of the serpins does support the idea that this protein family arose from an early recombination event which fused the amino and carboxyl domains. The structure of the carboxyl domain also suggests that an insertion subsequent to the fusion event contributed two strands of -sheet, which complemented three -sheet strands of the amino domain, to complete -sheet A, which is the central secondary structure feature of the serpins. Few of the introns lie between regions of secondary or tertiary structure, and it seems more likely that many were acquired subsequent to the early events of serpin evolution and have undergone multiple insertions, deletions, and migrations since, subject to the constraint of the serpin structure.Abbreviations Api -1-proteinase inhibitor (human) - Aci -1-antichymotrypsin (human) - Agt angiotensinogen (rat) - Oah ovalbumin (chicken) - Gyh gene y (chicken) - At3 antithrombin 3 (human) - Pi1 plasminogen activator inhibitor 1—endothelial (human) - Pi2 plasminogen activator inhibitor 2—placental (human) - Cli Cl inhibitor (human) - Apl antiplasmin (human) - Bz4 Z protein (barley).