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Evolutionary history of tissue kallikreins.

Pavlopoulou A, Pampalakis G, Michalopoulos I, Sotiropoulou G - PLoS ONE (2010)

Bottom Line: The chromosomal co-localization in a single cluster distinguishes KLKs from trypsin and other trypsin-like proteases which are spread in different genetic loci.All the defining features of the KLKs were further found to be conserved in the novel KLK protein sequences.The study of this unique family will further assist in selecting new model organisms for functional studies of proteolytic pathways involving KLKs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Greece.

ABSTRACT
The gene family of human kallikrein-related peptidases (KLKs) encodes proteins with diverse and pleiotropic functions in normal physiology as well as in disease states. Currently, the most widely known KLK is KLK3 or prostate-specific antigen (PSA) that has applications in clinical diagnosis and monitoring of prostate cancer. The KLK gene family encompasses the largest contiguous cluster of serine proteases in humans which is not interrupted by non-KLK genes. This exceptional and unique characteristic of KLKs makes them ideal for evolutionary studies aiming to infer the direction and timing of gene duplication events. Previous studies on the evolution of KLKs were restricted to mammals and the emergence of KLKs was suggested about 150 million years ago (mya). In order to elucidate the evolutionary history of KLKs, we performed comprehensive phylogenetic analyses of KLK homologous proteins in multiple genomes including those that have been completed recently. Interestingly, we were able to identify novel reptilian, avian and amphibian KLK members which allowed us to trace the emergence of KLKs 330 mya. We suggest that a series of duplication and mutation events gave rise to the KLK gene family. The prominent feature of the KLK family is that it consists of tandemly and uninterruptedly arrayed genes in all species under investigation. The chromosomal co-localization in a single cluster distinguishes KLKs from trypsin and other trypsin-like proteases which are spread in different genetic loci. All the defining features of the KLKs were further found to be conserved in the novel KLK protein sequences. The study of this unique family will further assist in selecting new model organisms for functional studies of proteolytic pathways involving KLKs.

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Related in: MedlinePlus

Schematic representation of the chromosomal arrangement of KLKs.The orientation and approximate position and size of the kallikrein genes. The KLK encoding genes are shown as filled arrowheads, whereas the KLK pseudogenes are represented by open arrowheads. The KLK2, KLK2-ps and KLK3 genes are indicated by red. Loci are drawn in approximate scale. On the left, a NCBI taxonomy-based cladogram shows the evolutionary relationships of taxa and the taxonomic classes.
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pone-0013781-g004: Schematic representation of the chromosomal arrangement of KLKs.The orientation and approximate position and size of the kallikrein genes. The KLK encoding genes are shown as filled arrowheads, whereas the KLK pseudogenes are represented by open arrowheads. The KLK2, KLK2-ps and KLK3 genes are indicated by red. Loci are drawn in approximate scale. On the left, a NCBI taxonomy-based cladogram shows the evolutionary relationships of taxa and the taxonomic classes.

Mentions: All identified sequences are depicted in Table S1. As shown in Figure 1, the amino acid residues corresponding to the active site residues (chymotrypsin numbering: His57, Asp102 and Ser195) are conserved among species. The core trypsin domain of the 260 retrieved sequences was used to reconstruct a maximum likelihood-based phylogenetic tree (Figure 2). The recently released zebrafinch and platypus genomes [30], [31] allowed us also to identify novel partial KLK-like sequences (zebra finch) (Table S1) which were not included in the phylogenetic analysis because they would decrease the resolution of the phylogenetic tree. In this tree, 13 coherent monophyletic branches were identified which permitted the preliminary classification of the candidate KLK protein sequences into 13 groups (Figure 2). Subsequently, a sample of 87 KLK protein sequences was chosen for more accurate phylogenetic analysis using the maximum likelihood method (Figure 3). This selection was done based on representative taxa (from the main taxonomic divisions). The generated tree is overall well-supported (Figure 3). The low bootstrap values in some deep-branching nodes suggest alternative branching. In the inferred phylogenetic tree, 13 highly resolved clades are distinguished which correspond to the classical KLKs (KLK1 to KLK3) and the other 12 KLK members (KLK4 to KLK15) (Figure 3). Interestingly, three reptilian KLK-related sequences appear to form their own separate clades, with relatively high support values, and they were arbitrarily referred to as “orphan KLKs” (Figures 2 and 3). Importantly, examination of the chromosomal localization of the KLK genes in different species reveals that the position and orientation of these genes are highly preserved (Figure 4). In addition, as is demonstrated in Figure S1 the splicing patterns are consistent between all KLK sequences, and the amino acid residues encompassing the active site are located in different exons as in human KLK genes.


Evolutionary history of tissue kallikreins.

Pavlopoulou A, Pampalakis G, Michalopoulos I, Sotiropoulou G - PLoS ONE (2010)

Schematic representation of the chromosomal arrangement of KLKs.The orientation and approximate position and size of the kallikrein genes. The KLK encoding genes are shown as filled arrowheads, whereas the KLK pseudogenes are represented by open arrowheads. The KLK2, KLK2-ps and KLK3 genes are indicated by red. Loci are drawn in approximate scale. On the left, a NCBI taxonomy-based cladogram shows the evolutionary relationships of taxa and the taxonomic classes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2967472&req=5

pone-0013781-g004: Schematic representation of the chromosomal arrangement of KLKs.The orientation and approximate position and size of the kallikrein genes. The KLK encoding genes are shown as filled arrowheads, whereas the KLK pseudogenes are represented by open arrowheads. The KLK2, KLK2-ps and KLK3 genes are indicated by red. Loci are drawn in approximate scale. On the left, a NCBI taxonomy-based cladogram shows the evolutionary relationships of taxa and the taxonomic classes.
Mentions: All identified sequences are depicted in Table S1. As shown in Figure 1, the amino acid residues corresponding to the active site residues (chymotrypsin numbering: His57, Asp102 and Ser195) are conserved among species. The core trypsin domain of the 260 retrieved sequences was used to reconstruct a maximum likelihood-based phylogenetic tree (Figure 2). The recently released zebrafinch and platypus genomes [30], [31] allowed us also to identify novel partial KLK-like sequences (zebra finch) (Table S1) which were not included in the phylogenetic analysis because they would decrease the resolution of the phylogenetic tree. In this tree, 13 coherent monophyletic branches were identified which permitted the preliminary classification of the candidate KLK protein sequences into 13 groups (Figure 2). Subsequently, a sample of 87 KLK protein sequences was chosen for more accurate phylogenetic analysis using the maximum likelihood method (Figure 3). This selection was done based on representative taxa (from the main taxonomic divisions). The generated tree is overall well-supported (Figure 3). The low bootstrap values in some deep-branching nodes suggest alternative branching. In the inferred phylogenetic tree, 13 highly resolved clades are distinguished which correspond to the classical KLKs (KLK1 to KLK3) and the other 12 KLK members (KLK4 to KLK15) (Figure 3). Interestingly, three reptilian KLK-related sequences appear to form their own separate clades, with relatively high support values, and they were arbitrarily referred to as “orphan KLKs” (Figures 2 and 3). Importantly, examination of the chromosomal localization of the KLK genes in different species reveals that the position and orientation of these genes are highly preserved (Figure 4). In addition, as is demonstrated in Figure S1 the splicing patterns are consistent between all KLK sequences, and the amino acid residues encompassing the active site are located in different exons as in human KLK genes.

Bottom Line: The chromosomal co-localization in a single cluster distinguishes KLKs from trypsin and other trypsin-like proteases which are spread in different genetic loci.All the defining features of the KLKs were further found to be conserved in the novel KLK protein sequences.The study of this unique family will further assist in selecting new model organisms for functional studies of proteolytic pathways involving KLKs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Greece.

ABSTRACT
The gene family of human kallikrein-related peptidases (KLKs) encodes proteins with diverse and pleiotropic functions in normal physiology as well as in disease states. Currently, the most widely known KLK is KLK3 or prostate-specific antigen (PSA) that has applications in clinical diagnosis and monitoring of prostate cancer. The KLK gene family encompasses the largest contiguous cluster of serine proteases in humans which is not interrupted by non-KLK genes. This exceptional and unique characteristic of KLKs makes them ideal for evolutionary studies aiming to infer the direction and timing of gene duplication events. Previous studies on the evolution of KLKs were restricted to mammals and the emergence of KLKs was suggested about 150 million years ago (mya). In order to elucidate the evolutionary history of KLKs, we performed comprehensive phylogenetic analyses of KLK homologous proteins in multiple genomes including those that have been completed recently. Interestingly, we were able to identify novel reptilian, avian and amphibian KLK members which allowed us to trace the emergence of KLKs 330 mya. We suggest that a series of duplication and mutation events gave rise to the KLK gene family. The prominent feature of the KLK family is that it consists of tandemly and uninterruptedly arrayed genes in all species under investigation. The chromosomal co-localization in a single cluster distinguishes KLKs from trypsin and other trypsin-like proteases which are spread in different genetic loci. All the defining features of the KLKs were further found to be conserved in the novel KLK protein sequences. The study of this unique family will further assist in selecting new model organisms for functional studies of proteolytic pathways involving KLKs.

Show MeSH
Related in: MedlinePlus