Phylogeny of the Serpin Superfamily: Implications of Patterns of Amino Acid Conservation for Structure and Function

Abstract

We present a comprehensive alignment and phylogenetic analysis of the serpins, a superfamily of proteins with known members in higher animals, nematodes, insects, plants, and viruses. We analyze, compare, and classify 219 proteins representative of eight major and eight minor subfamilies, using a novel technique of consensus analysis. Patterns of sequence conservation characterize the family as a whole, with a clear relationship to the mechanism of function. Variations of these patterns within phylogenetically distinct groups can be correlated with the divergence of structure and function. The goals of this work are to provide a carefully curated alignment of serpin sequences, to describe patterns of conservation and divergence, and to derive a phylogenetic tree expressing the relationships among the members of this family. We extend earlier studies by Huber and Carrell as well as by Marshall, after whose publication the serpin family has grown functionally, taxonomically, and structurally. We used gene and protein sequence data, crystal structures, and chromosomal location where available. The results illuminate structure-function relationships in serpins, suggesting roles for conserved residues in the mechanism of conformational change. The phylogeny provides a rational evolutionary framework to classify serpins and enables identification of conserved amino acids. Patterns of conservation also provide an initial point of comparison for genes identified by the various genome projects. New homologs emerging from sequencing projects can either take their place within the current classification or, if necessary, extend it.

Identification and characterization of a new member of serpin family- HongrES1 in rat epididymis

“…Apart from the strange RCL sequence, HongrES1 had characteristics of alpha1-antitrypsin: Thr and Leu were at P1 and P1' of RCL, and the protein contained most of the conserved residues [10]. But whether HongrES1 has inhibitory activity or not remains to be analyzed by experiments.…”

Control of granzymes by serpins

“…Irving et al 1 proposed a system of 16 clades based on amino acid phylogeny, which has since been widely implemented. Under this system, the plant and insect serpins fall into a single clade each, whereas viral sequences are divided into two clades.…”

“…1,2 Serpins function as intracellular or extracellular regulators of a wide range of physiological processes such as complement activation, blood coagulation and apoptosis. Within the vertebrate immune system, they control proteases of the classical and innate complement systems, and are also potent inhibitors of many leukocyte granule proteases.…”

Translating Lung Function Genome-Wide Association Study (GWAS) Findings

“…A1AT is a member of the serine protease inhibitor superfamily (SERPINS) and phylogenetic analyses indicate its evolutionary conservation in higher animals, nematodes, insects, plants, and viruses (Irving, Pike, Lesk, & Whisstock, 2000). The path that led to the discovery of A1AT deficiency as a risk factor for emphysema has a long history.…”