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How immune peptidases change specificity: cathepsin G gained tryptic function but lost efficiency during primate evolution.

ABSTRACT: Cathepsin G is a major secreted serine peptidase of neutrophils and mast cells. Studies in Ctsg-null mice suggest that cathepsin G supports antimicrobial defenses but can injure host tissues. The human enzyme has an unusual "Janus-faced" ability to cleave peptides at basic (tryptic) as well as aromatic (chymotryptic) sites. Tryptic activity has been attributed to acidic Glu(226) in the primary specificity pocket and underlies proposed important functions, such as activation of prourokinase. However, most mammals, including mice, substitute Ala(226) for Glu(226), suggesting that human tryptic activity may be anomalous. To test this hypothesis, human cathepsin G was compared with mouse wild-type and humanized active site mutants, revealing that mouse primary specificity is markedly narrower than that of human cathepsin G, with much greater Tyr activity and selectivity and near absence of tryptic activity. It also differs from human in resisting tryptic peptidase inhibitors (e.g., aprotinin), while favoring angiotensin destruction at Tyr(4) over activation at Phe(8). Ala(226)Glu mutants of mouse cathepsin G acquire tryptic activity and human ability to activate prourokinase. Phylogenetic analysis reveals that the Ala(226)Glu missense mutation appearing in primates 31-43 million years ago represented an apparently unprecedented way to create tryptic activity in a serine peptidase. We propose that tryptic activity is not an attribute of ancestral mammalian cathepsin G, which was primarily chymotryptic, and that primate-selective broadening of specificity opposed the general trend of increased specialization by immune peptidases and allowed acquisition of new functions.

SUBMITTER: Raymond WW

PROVIDER: S-EPMC3954857 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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How immune peptidases change specificity: cathepsin G gained tryptic function but lost efficiency during primate evolution.

Raymond Wilfred W WW Trivedi Neil N NN Makarova Anastasia A Ray Manisha M Craik Charles S CS Caughey George H GH

Journal of immunology (Baltimore, Md. : 1950) 20101001 9

Cathepsin G is a major secreted serine peptidase of neutrophils and mast cells. Studies in Ctsg-null mice suggest that cathepsin G supports antimicrobial defenses but can injure host tissues. The human enzyme has an unusual "Janus-faced" ability to cleave peptides at basic (tryptic) as well as aromatic (chymotryptic) sites. Tryptic activity has been attributed to acidic Glu(226) in the primary specificity pocket and underlies proposed important functions, such as activation of prourokinase. Howe ...[more]

PMID: 20889553

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Project description:BackgroundUtilizing unique carbohydrates or utilizing them more efficiently help bacteria expand and colonize new niches. Horizontal gene transfer (HGT) of catabolic systems is a powerful mechanism by which bacteria can acquire new phenotypic traits that can increase survival and fitness in different niches. In this work, we examined carbon catabolism diversity among Vibrio parahaemolyticus, a marine species that is also an important human and fish pathogen.ResultsPhenotypic differences in carbon utilization between Vibrio parahaemolyticus strains lead us to examine genotypic differences in this species and the family Vibrionaceae in general. Bioinformatics analysis showed that the ability to utilize D-galactose was present in all V. parahaemolyticus but at least two distinct transporters were present; a major facilitator superfamily (MFS) transporter and a sodium/galactose transporter (SGLT). Growth and genetic analyses demonstrated that SGLT was a more efficient transporter of D-galactose and was the predominant type among strains. Phylogenetic analysis showed that D-galactose gene galM was acquired multiples times within the family Vibrionaceae and was transferred between distantly related species. The ability to utilize D-gluconate was universal within the species. Deletion of eda (VP0065), which encodes aldolase, a key enzyme in the Entner-Doudoroff (ED) pathway, reached a similar biomass to wild type when grown on D-gluconate as a sole carbon source. Two additional eda genes were identified, VPA1708 (eda2) associated with a D-glucuronate cluster and VPA0083 (eda3) that clustered with an oligogalacturonide (OGA) metabolism cluster. EDA2 and EDA3 were variably distributed among the species. A metabolic island was identified that contained citrate fermentation, L-rhamnose and OGA metabolism clusters as well as a CRISPR-Cas system. Phylogenetic analysis showed that CitF and RhaA had a limited distribution among V. parahaemolyticus, and RhaA was acquired at least three times. Within V. parahaemolyticus, two different regions contained the gene for L-arabinose catabolism and most strains had the ability to catabolism this sugar.ConclusionOur data suggest that horizontal transfer of metabolic systems among Vibrionaceae is an important source of metabolic diversity. This work identified four EDA homologues suggesting that the ED pathway plays a significant role in metabolism. We describe previously uncharacterized metabolism islands that were hotspots for the gain and loss of functional modules likely mediated by transposons.

Dataset Information

How immune peptidases change specificity: cathepsin G gained tryptic function but lost efficiency during primate evolution.

Publications

How immune peptidases change specificity: cathepsin G gained tryptic function but lost efficiency during primate evolution.

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