Evolution of the plasma and tissue kallikreins, and their alternative splicing isoforms

PLoS One. 2013 Jul 10;8(7):e68074. doi: 10.1371/journal.pone.0068074. Print 2013.

Abstract

Kallikreins are secreted serine proteases with important roles in human physiology. Human plasma kallikrein, encoded by the KLKB1 gene on locus 4q34-35, functions in the blood coagulation pathway, and in regulating blood pressure. The human tissue kallikrein and kallikrein-related peptidases (KLKs) have diverse expression patterns and physiological roles, including cancer-related processes such as cell growth regulation, angiogenesis, invasion, and metastasis. Prostate-specific antigen (PSA), the product of the KLK3 gene, is the most widely used biomarker in clinical practice today. A total of 15 KLKs are encoded by the largest contiguous cluster of protease genes in the human genome (19q13.3-13.4), which makes them ideal for evolutionary analysis of gene duplication events. Previous studies on the evolution of KLKs have traced mammalian homologs as well as a probable early origin of the family in aves, amphibia and reptilia. The aim of this study was to address the evolutionary and functional relationships between tissue KLKs and plasma kallikrein, and to examine the evolution of alternative splicing isoforms. Sequences of plasma and tissue kallikreins and their alternative transcripts were collected from the NCBI and Ensembl databases, and comprehensive phylogenetic analysis was performed by Bayesian as well as maximum likelihood methods. Plasma and tissue kallikreins exhibit high sequence similarity in the trypsin domain (>50%). Phylogenetic analysis indicates an early divergence of KLKB1, which groups closely with plasminogen, chymotrypsin, and complement factor D (CFD), in a monophyletic group distinct from trypsin and the tissue KLKs. Reconstruction of the earliest events leading to the diversification of the tissue KLKs is not well resolved, indicating rapid expansion in mammals. Alternative transcripts of each KLK gene show species-specific divergence, while examination of sequence conservation indicates that many annotated human KLK isoforms are missing the catalytic triad that is crucial for protease activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing* / genetics
  • Amino Acid Sequence
  • Conserved Sequence
  • Evolution, Molecular*
  • Humans
  • Molecular Sequence Data
  • Phylogeny
  • Plasma Kallikrein / chemistry
  • Plasma Kallikrein / genetics*
  • Protein Conformation
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Structure, Tertiary
  • Sequence Homology
  • Tissue Kallikreins / chemistry
  • Tissue Kallikreins / genetics*

Substances

  • Protein Isoforms
  • Plasma Kallikrein
  • Tissue Kallikreins

Grants and funding

This work was financially supported by the Commission of the European Community through the INsPiRE project (EU-FP7-REGPOT-2011-1, proposal 284460) (http://ec.europa.eu/research/index.cfm). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.