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???displayArticle.abstract??? Cathepsin L family, an important cysteine protease found in lysosomes, is categorized into cathepsins B, F, H, K, L, S, and W in vertebrates. This categorization is based on their sequence alignment and traditional functional classification, but the evolutionary relationship of family members is unclear. This study determined the evolutionary relationship of cathepsin L family genes in vertebrates through phylogenetic construction. Results showed that cathepsins F, H, S and K, and L and V were chronologically diverged. Tandem-repeat duplication was found to occur in the evolutionary history of cathepsin L family. Cathepsin L in zebrafish, cathepsins S and K in xenopus, and cathepsin L in mice and rats underwent evident tandem-repeat events. Positive selection was detected in cathepsin L-like members in mice and rats, and amino acid sites under positive selection pressure were calculated. Most of these sites appeared at the connection of secondary structures, suggesting that the sites may slightly change spatial structure. Severe positive selection was also observed in cathepsin V (L2) of primates, indicating that this enzyme had some special functions. Our work provided a brief evolutionary history of cathepsin L family and differentiated cathepsins S and K from cathepsin L based on vertebrate appearance. Positive selection was the specific cause of differentiation of cathepsin L family genes, confirming that gene function variation after expansion events was related to interactions with the environment and adaptability.
Figure 1. Phylogenetic tree of cathepsin L-like family. The phylogeny of 114 cathepsin L-like family genes from other species was constructed using MrBayes. Numbers at nodes are posterior probabilities from Bayesian inference. Aca (Anolis carolinensis, Lizard), Bfl (Branchiostoma floridae, Lancelet), Ciona (Ciona intestinalis, vase tunicatea), Dre (Danio rerio, Zebrafish), Gac (Gasterosteus aculeatus, Stickleback), Gga (Gallus gallus, Chicken), Hsa (Homo sapiens, Human), Mmu (Mus musculus, Mouse), Pma (Petromyzon marinus, Lamprey), Sus (Sus scrofa, Pig), and Xtr (Xenopus tropicalis, Frog).
Figure 2. Selection of cathepsin L-like family estimated by the free ratio model. Branches with ω > 1 are shown as thick lines. The estimated ω ratios are given above the branches and numbers of nonsynonymous, and synonymous changes are given under the branches. Bta (Bos Taurus, Cow), Cfa (Canis familiaris, Dog), Cpo (Cavia porcellus, Guinea pig), Hsa (Homo sapiens, Human), Mmu (Mus musculus, Mouse), Ocu (Oryctolagus cuniculus, Rabbit), Ptr (Pan troglodytes, Chimpanzee), Rno (Rattus norvegicus, Rat), and Sus (Sus scrofa, Pig).
Figure 3. Protein structure of cathepsin L-like family. (a) Model of CL protein based on homology modeling. (b) Positions of type-1 sites in the model. Type-1 sites are shown as spheres; SRS, red; helix F-G, green. (c) Positions of type-II sites in the model. Type-II sites are shown as spheres colored as in (B). (D) Example of multialignment of CL family amino acid sequences. Conserved sites are shaded, and the meaning of each symbol is given in the box.
Figure 4. Motif analysis of cathepsin L family genes. Motif type and length are represented by different colors and box sizes.
Figure 5. The skeleton of evolutionary process of cathepsin L (L-like) family.
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