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Evolution of C, D and S-type cystatins in mammals: an extensive gene duplication in primates.

de Sousa-Pereira P, Abrantes J, Pinheiro A, Colaço B, Vitorino R, Esteves PJ - PLoS ONE (2014)

Bottom Line: On the other hand, D and S-type cystatins are mainly retrieved from Primates, and especially the evolution of S-type cystatins seems to be a dynamic process as seen in Pongo abelii genome where several copies of CST1-like gene (cystatin SN) were found.These results suggest that the D and S type cystatins have emerged before the mammalian radiation and were retained only in Primates and Rodents.The factors that led to the appearance of a group of saliva-specific cystatins in Primates and its rapid evolution remain undetermined, but may be associated with an adaptive advantage.

View Article: PubMed Central - PubMed

Affiliation: QOPNA, Centro de Espectrometria de Massa, Departamento de Química, Universidade de Aveiro, Aveiro, Portugal; CIBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, InBio, Laboratório Associado, Universidade do Porto, Vairão, Portugal.

ABSTRACT
Cystatins are a family of inhibitors of cysteine peptidases that comprises the salivary cystatins (D and S-type cystatins) and cystatin C. These cystatins are encoded by a multigene family (CST3, CST5, CST4, CST1 and CST2) organized in tandem in the human genome. Their presence and functional importance in human saliva has been reported, however the distribution of these proteins in other mammals is still unclear. Here, we performed a proteomic analysis of the saliva of several mammals and studied the evolution of this multigene family. The proteomic analysis detected S-type cystatins (S, SA, and SN) in human saliva and cystatin D in rat saliva. The evolutionary analysis showed that the cystatin C encoding gene is present in species of the most representative mammalian groups, i.e. Artiodactyla, Rodentia, Lagomorpha, Carnivora and Primates. On the other hand, D and S-type cystatins are mainly retrieved from Primates, and especially the evolution of S-type cystatins seems to be a dynamic process as seen in Pongo abelii genome where several copies of CST1-like gene (cystatin SN) were found. In Rodents, a group of cystatins previously identified as D and S has also evolved. Despite the high divergence of the amino acid sequence, their position in the phylogenetic tree and their genome organization suggests a common origin with those of the Primates. These results suggest that the D and S type cystatins have emerged before the mammalian radiation and were retained only in Primates and Rodents. Although the mechanisms driving the evolution of cystatins are unknown, it seems to be a dynamic process with several gene duplications evolving according to the birth-and-death model of evolution. The factors that led to the appearance of a group of saliva-specific cystatins in Primates and its rapid evolution remain undetermined, but may be associated with an adaptive advantage.

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Amino acid composition of cystatins.Homo sapiens cystatin C (P01034); Bos taurus cystatin C (P01035); Rattus norvegicus cystatin C (P14841); Canis lupus familiaris cystatin C (J9NS29); Homo sapiens cystatin D (P28325); Callithrix jacchus cystatin D (ENSCJAP00000001156); Macaca mulatta cystatin D (G7N352); Homo sapiens cystatin SN (P01037); Pan troglodytes cystatin SN (H2QK35); Homo sapiens cystatin S (P01036); Pan troglodytes cystatin S (H2QK34); Homo sapiens cystatin SA (P09228); Pan troglodytes cystatin SA (H2QK36) and Rattus norvegicus cystatin S (P19313). Filled grey boxes indicate conserved amino acid motifs; empty boxes indicate conserved amino acids characteristic of each cystatin; asterisks (*) mark the codons on CST3 under negative selection.
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pone-0109050-g002: Amino acid composition of cystatins.Homo sapiens cystatin C (P01034); Bos taurus cystatin C (P01035); Rattus norvegicus cystatin C (P14841); Canis lupus familiaris cystatin C (J9NS29); Homo sapiens cystatin D (P28325); Callithrix jacchus cystatin D (ENSCJAP00000001156); Macaca mulatta cystatin D (G7N352); Homo sapiens cystatin SN (P01037); Pan troglodytes cystatin SN (H2QK35); Homo sapiens cystatin S (P01036); Pan troglodytes cystatin S (H2QK34); Homo sapiens cystatin SA (P09228); Pan troglodytes cystatin SA (H2QK36) and Rattus norvegicus cystatin S (P19313). Filled grey boxes indicate conserved amino acid motifs; empty boxes indicate conserved amino acids characteristic of each cystatin; asterisks (*) mark the codons on CST3 under negative selection.

Mentions: The alignment of the amino acid sequences of C, D and S-type cystatins allowed the detection of amino acid motifs that could be relevant to their functional role (Figure 2). For cystatins, three motifs that are important for the inhibition of cysteine peptidases (CPs) have been described: one N-terminal G residue and the QXVXG and PW motifs [8]; these were observed in almost every cystatin sequence retrieved (Figure 2). Moreover, by looking at the amino acid sequences, the different cystatins present specific amino acid motifs that allow their distinction (Figure 2). However, the S-type cystatins, S, SA and SN, share several amino acid substitutions that hamper their assignment as different types. From the amino acid alignment it was also noticeable that the rat cystatin S is highly divergent, being substantially different from their Primates’ counterparts. The tests for selective pressures for cystatin C showed that only ∼30% of randomly positioned codons are under negative selection (Figure 2).


Evolution of C, D and S-type cystatins in mammals: an extensive gene duplication in primates.

de Sousa-Pereira P, Abrantes J, Pinheiro A, Colaço B, Vitorino R, Esteves PJ - PLoS ONE (2014)

Amino acid composition of cystatins.Homo sapiens cystatin C (P01034); Bos taurus cystatin C (P01035); Rattus norvegicus cystatin C (P14841); Canis lupus familiaris cystatin C (J9NS29); Homo sapiens cystatin D (P28325); Callithrix jacchus cystatin D (ENSCJAP00000001156); Macaca mulatta cystatin D (G7N352); Homo sapiens cystatin SN (P01037); Pan troglodytes cystatin SN (H2QK35); Homo sapiens cystatin S (P01036); Pan troglodytes cystatin S (H2QK34); Homo sapiens cystatin SA (P09228); Pan troglodytes cystatin SA (H2QK36) and Rattus norvegicus cystatin S (P19313). Filled grey boxes indicate conserved amino acid motifs; empty boxes indicate conserved amino acids characteristic of each cystatin; asterisks (*) mark the codons on CST3 under negative selection.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4201479&req=5

pone-0109050-g002: Amino acid composition of cystatins.Homo sapiens cystatin C (P01034); Bos taurus cystatin C (P01035); Rattus norvegicus cystatin C (P14841); Canis lupus familiaris cystatin C (J9NS29); Homo sapiens cystatin D (P28325); Callithrix jacchus cystatin D (ENSCJAP00000001156); Macaca mulatta cystatin D (G7N352); Homo sapiens cystatin SN (P01037); Pan troglodytes cystatin SN (H2QK35); Homo sapiens cystatin S (P01036); Pan troglodytes cystatin S (H2QK34); Homo sapiens cystatin SA (P09228); Pan troglodytes cystatin SA (H2QK36) and Rattus norvegicus cystatin S (P19313). Filled grey boxes indicate conserved amino acid motifs; empty boxes indicate conserved amino acids characteristic of each cystatin; asterisks (*) mark the codons on CST3 under negative selection.
Mentions: The alignment of the amino acid sequences of C, D and S-type cystatins allowed the detection of amino acid motifs that could be relevant to their functional role (Figure 2). For cystatins, three motifs that are important for the inhibition of cysteine peptidases (CPs) have been described: one N-terminal G residue and the QXVXG and PW motifs [8]; these were observed in almost every cystatin sequence retrieved (Figure 2). Moreover, by looking at the amino acid sequences, the different cystatins present specific amino acid motifs that allow their distinction (Figure 2). However, the S-type cystatins, S, SA and SN, share several amino acid substitutions that hamper their assignment as different types. From the amino acid alignment it was also noticeable that the rat cystatin S is highly divergent, being substantially different from their Primates’ counterparts. The tests for selective pressures for cystatin C showed that only ∼30% of randomly positioned codons are under negative selection (Figure 2).

Bottom Line: On the other hand, D and S-type cystatins are mainly retrieved from Primates, and especially the evolution of S-type cystatins seems to be a dynamic process as seen in Pongo abelii genome where several copies of CST1-like gene (cystatin SN) were found.These results suggest that the D and S type cystatins have emerged before the mammalian radiation and were retained only in Primates and Rodents.The factors that led to the appearance of a group of saliva-specific cystatins in Primates and its rapid evolution remain undetermined, but may be associated with an adaptive advantage.

View Article: PubMed Central - PubMed

Affiliation: QOPNA, Centro de Espectrometria de Massa, Departamento de Química, Universidade de Aveiro, Aveiro, Portugal; CIBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, InBio, Laboratório Associado, Universidade do Porto, Vairão, Portugal.

ABSTRACT
Cystatins are a family of inhibitors of cysteine peptidases that comprises the salivary cystatins (D and S-type cystatins) and cystatin C. These cystatins are encoded by a multigene family (CST3, CST5, CST4, CST1 and CST2) organized in tandem in the human genome. Their presence and functional importance in human saliva has been reported, however the distribution of these proteins in other mammals is still unclear. Here, we performed a proteomic analysis of the saliva of several mammals and studied the evolution of this multigene family. The proteomic analysis detected S-type cystatins (S, SA, and SN) in human saliva and cystatin D in rat saliva. The evolutionary analysis showed that the cystatin C encoding gene is present in species of the most representative mammalian groups, i.e. Artiodactyla, Rodentia, Lagomorpha, Carnivora and Primates. On the other hand, D and S-type cystatins are mainly retrieved from Primates, and especially the evolution of S-type cystatins seems to be a dynamic process as seen in Pongo abelii genome where several copies of CST1-like gene (cystatin SN) were found. In Rodents, a group of cystatins previously identified as D and S has also evolved. Despite the high divergence of the amino acid sequence, their position in the phylogenetic tree and their genome organization suggests a common origin with those of the Primates. These results suggest that the D and S type cystatins have emerged before the mammalian radiation and were retained only in Primates and Rodents. Although the mechanisms driving the evolution of cystatins are unknown, it seems to be a dynamic process with several gene duplications evolving according to the birth-and-death model of evolution. The factors that led to the appearance of a group of saliva-specific cystatins in Primates and its rapid evolution remain undetermined, but may be associated with an adaptive advantage.

Show MeSH