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. 2007 Nov 1;179(9):6072-9.
doi: 10.4049/jimmunol.179.9.6072.

Mast Cell Alpha and Beta Tryptases Changed Rapidly During Primate Speciation and Evolved From Gamma-Like Transmembrane Peptidases in Ancestral Vertebrates

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Free PMC article

Mast Cell Alpha and Beta Tryptases Changed Rapidly During Primate Speciation and Evolved From Gamma-Like Transmembrane Peptidases in Ancestral Vertebrates

Neil N Trivedi et al. J Immunol. .
Free PMC article

Abstract

Human mast cell tryptases vary strikingly in secretion, catalytic competence, and inheritance. To explore the basis of variation, we compared genes from a range of primates, including humans, great apes (chimpanzee, gorilla, orangutan), Old- and New-World monkeys (macaque and marmoset), and a prosimian (galago), tracking key changes. Our analysis reveals that extant soluble tryptase-like proteins, including alpha- and beta-like tryptases, mastins, and implantation serine proteases, likely evolved from membrane-anchored ancestors because their more deeply rooted relatives (gamma tryptases, pancreasins, prostasins) are type I transmembrane peptidases. Function-altering mutations appeared at widely separated times during primate speciation, with tryptases evolving by duplication, gene conversion, and point mutation. The alpha-tryptase Gly(216)Asp catalytic domain mutation, which diminishes activity, is present in macaque tryptases, and thus arose before great apes and Old World monkeys shared an ancestor, and before the alphabeta split. However, the Arg(-3)Gln processing mutation appeared recently, affecting only human alpha. By comparison, the transmembrane gamma-tryptase gene, which anchors the telomeric end of the multigene tryptase locus, changed little during primate evolution. Related transmembrane peptidase genes were found in reptiles, amphibians, and fish. We identified soluble tryptase-like genes in the full spectrum of mammals, including marsupial (opossum) and monotreme (platypus), but not in nonmammalian vertebrates. Overall, our analysis suggests that soluble tryptases evolved rapidly from membrane-anchored, two-chain peptidases in ancestral vertebrates into soluble, single-chain, self-compartmentalizing, inhibitor-resistant oligomers expressed primarily by mast cells, and that much of present numerical, behavioral, and genetic diversity of alpha- and beta-like tryptases was acquired during primate evolution.

Figures

FIGURE 1
FIGURE 1
Alignment of primate α-like/β-like/δ-like tryptases. Examples of tryptases sequenced or deduced for this work are aligned as indicated and compared with human βI, αII, and δ tryptases and mouse mast cell protease (MMCP) 6 and 7 tryptases. See Table I for GenBank identifiers. Hyphens (-) indicate amino acid identity compared with corresponding residues in human βI tryptase. Asterisks (*) identify gaps in the alignment. Symbol meanings: #, “catalytic triad” residues common to all active serine peptidases; %, conserved “specificity triad” residues typical of most serine peptidases of tryptic specificity; +, the predicted sites of N-glycosylation conserved in all of these enzymes; underlined residues indicate loops involved in subunit contacts.
FIGURE 2
FIGURE 2
Tree of α-like/β-like tryptases. Potential phylogenetic relationships between classic murine and primate soluble mast cell tryptases, including proteins newly sequenced or deduced for this study, are probed with this rooted dendrogram generated by UPGMA with 500 iterations of bootstrap resampling. The tree also is a template for tracking other tryptases with the propeptide processing mutation of human α (R-3Q, heavy solid line) as well as the catalytic domain mutation (G215D, hatched line). Proposed branch points for α and β clades are identified by the appropriate symbol. Sources of primate tryptase sequences are in Table I. Nonprimate sources are as follows: opossum (M. domestica, deduced from whole genome shotgun sequence AAFR03046243), rat Mcpt6 and 7 (R. norvegicus, AAB48262 and AAB48263), mouse Mcpt6 and 7 (M. musculus, P21845 and Q02844). Note that the αβ primate tryptases share ancestry more recently with rodent Mcpt6 tryptases than with Mcpt7, that key α mutations appeared at times widely separated in primate evolution, and that the αβ dichotomy is recent and only evident among great apes.
FIGURE 3
FIGURE 3
Alignment of γ tryptases. Hyphens (-) indicate amino acid identity compared with the corresponding residues in human γI tryptase. See Table I for identifiers of primate GenBank files, which contain full genomic sequence. Mouse (M. musculus) and rat (R. norvegicus) sequences are from NP_036164 and NM_175593, respectively. Asterisks (*) identify gaps in the alignment, the largest of which is in mouse and rat prosequence, corresponding to an exon that is transcribed in human and, by homology, other primate γ tryptases but not in murine γ genes. Symbol meanings: @, an absolutely conserved cysteine via which the propeptide remains linked to the catalytic domain after cleavage-activation between Arg-1 and Ile +1 to yield two-chain mature enzymes; underlined residues comprise a predicted transmembrane segment present in γ but not soluble tryptases; the meanings of #, %, and + symbols are as in Fig. 1.
FIGURE 4
FIGURE 4
Tree of vertebrate tryptase-like proteases. This rooted dendrogram was prepared by UPGMA with 500 iterations of bootstrap resampling. Refer to Table I for GenBank sources of galago, rhesus, and human γ tryptases and rhesus ISP2, to Fig. 3 for GenBank sources of mouse and rat γ tryptase, and to Fig. 2 for GenBank sources of opossum tryptase and rat and mouse Mcpt7 and Mcpt6. Other sequences were obtained as follows: frog channel-activating peptidase (CAP) 1 (Xenopus laevis, AAB96905), lizard, opossum, dog, cat, mouse, rat, rhesus, orangutan, chimpanzee, and human prostasin (Anolis carolinensis DS229345; M. domestica XP_001372224; C. familiaris XP_848861; Felis catus AANG01151030; M. musculus NM_133351; R. norvegicus AAG32641; Macaca mulatta XP_001112376; Pongo pygmaeus abelii CAH90878; Pan troglodytes XM_001157456; Homo sapiens NM_002773), lizard, mouse, rat, horse, dog, marmoset, rhesus, chimpanzee, and human pancreasin (A. carolinensis AAWZ01023110; M. musculus NM_175440; R. norvegicus NM_182949; and E. caballus AAWR01029521; C. familiaris AAEX02025250; C. jacchus contig 2675.45 (http://genome.wustl.edu); M. mulatta XM_001086389; Pan troglodytes XP_510751, Homo sapiens NM_031948), horse γ tryptase (E. caballus AAWR01029469), platypus tryptase-like protein 1 and 2 (O. anatinus AAPN01127233 and AAPN01196394), mouse, rat, and squirrel ISP2 (M. musculus AAK15264, R. norvegicus XP_220240, and Spermophilus tridecemlineatus AAQQ01728300), mouse, dog, cattle, and pig mastin (M. musculus AAS21652; C. familiaris P19236; B. taurus XM_869964; S. scrofa NP_998959), bat, hedgehog, horse, dog, pig, gerbil, sheep 1, sheep 2, cattle 1, and cattle 2 tryptase (M. lucifugus AAPE01472347; E. europaeus AANN01723492; E. caballus AJ515902; C. familiaris M24664; S. scrofa NP_999356; M. unguiculatus D31789; O. aries Y18223 and Y18224; B. taurus NP_776627 and AAFC03119556).
FIGURE 5
FIGURE 5
Proposed origins of human tryptases. Pseudogenes or catalytically flawed tryptases are shown in gray. Numbers 1−5 identify an ordered sequence of duplications, starting from an ancestral γ-like gene in early mammals, and giving rise to the current diversity of soluble human tryptase and tryptase-like genes. Upward arrows indicate proposed gene conversion events leading to the creation of the δ chimera and to allelic disparity of α and βI genes at the TPSAB1 locus.

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