Mutational Tail Loss Is an Evolutionary Mechanism for Liberating Marapsins and Other Type I Serine Proteases from Transmembrane Anchors

Raman, Kavita; Trivedi, Neil N.; Raymond, Wilfred W.; Ganesan, Rajkumar; Kirchhofer, Daniel; Verghese, George M.; Craik, Charles S.; Schneider, Eric L.; Nimishakavi, Shilpa; Caughey, George H.

doi:10.1074/jbc.m112.449033

Cited by 5 publications

(3 citation statements)

References 42 publications

(71 reference statements)

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“…Of these, several have already been knocked out in the mouse. It was determined that Prss16, Prss27, Prss35, and Tmprss4 have no abnormal phenotype [25][26][27] and Prss1, Prss8, Prss12, Prss56, Tmprss2, Tmprss3, Tmprss6, Tmprss11a, and Tmprss13 have non-reproductive phenotypes [27][28][29][30][31][32][33][34][35]. Although a functional requirement for Prss41 has not been determined through a mouse model, it has been shown to be testis-specific, predominantly expressed in the plasma membrane of spermatogonia and Sertoli cells in the basal compartment, and exhibits an intracellular localization in spermatocytes and spermatids in the adluminal compartment of the seminiferous tubules [36].…”

Section: Introductionmentioning

confidence: 99%

The testis-specific serine proteases PRSS44, PRSS46, and PRSS54 are dispensable for male mouse fertility†

Holcomb

Oura

Nozawa

et al. 2019

Biology of Reproduction

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High-throughput transcriptomics and proteomics approaches have recently identified a large number of germ cell–specific genes with many that remain to be studied through functional genetics approaches. Serine proteases (PRSS) constitute nearly one-third of all proteases, and, in our bioinformatics screens, we identified many that are testis specific. In this study, we chose to focus on Prss44, Prss46, and Prss54, which we confirmed as testis specific in mouse and human. Based on the analysis of developmental expression in the mouse, expression of all four genes is restricted to the late stage of spermatogenesis concomitant with a potential functional role in spermiogenesis, spermiation, or sperm function. To best understand the male reproductive requirement and functional roles of these serine proteases, each gene was individually ablated by CRISPR/Cas9-mediated ES cell or zygote approach. Homozygous deletion mutants for each gene were obtained and analyzed for phenotypic changes. Analyses of testis weights, testis and epididymis histology, sperm morphology, and fertility revealed no significant differences in Prss44, Prss46, and Prss54 knockout mice in comparison to controls. Our results thereby demonstrate that these genes are not required for normal fertility in mice, although do not preclude the possibility that these genes may function in a redundant manner. Elucidating the individual functional requirement or lack thereof of these novel genes is necessary to build a better understanding of the factors underlying spermatogenesis and sperm maturation, which has implications in understanding the etiology of male infertility and the development of male contraceptives.

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Section: Introductionmentioning

confidence: 99%

The testis-specific serine proteases PRSS44, PRSS46, and PRSS54 are dispensable for male mouse fertility†

Holcomb

Oura

Nozawa

et al. 2019

Biology of Reproduction

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“…PRSS27 encodes for marapsin, a tryptic serine protease acting on synthetic tetrapeptide substrates but with no general protease activity and with an unusual resistance to inhibitors such as aprotinin, serum serpins, and soybean trypsin inhibitor. 32 It has been suggested that the active site is partially blocked and does not allow access to large substrates and inhibitors. DPP7 (Dipeptidyl Peptidase 7) gene encodes for a serine aminopeptidase that cleaves dipeptides from the N-terminal of proteins that have a proline at the penultimate position.…”

Section: Resultsmentioning

confidence: 99%

Temporary serine protease inhibition and the role of SPINK2 in human bone marrow

et al. 2023

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“…Although being a transmembrane protein on first inspection would seem to place γ-tryptases into a class of peptidases not closely related to soluble tryptases, phylogenetic analysis suggests that soluble mast cell tryptases evolved from γ-like ancestral transmembrane proteins early in mammalian evolution (Trivedi et al, 2007). In further support of such a transition, the example of marapsin suggests a rather facile, one-step evolutionary pathway for converting a type 1 transmembrane tryptic protease to its soluble homologue (Raman et al, 2013). The standard topology of type I proteins predicts that γ-tryptase is anchored to the inside of the secretory granule lipid bilayer (Caughey et al, 2000a).…”

Section: Tryptasesmentioning

confidence: 97%

Mast cell proteases as pharmacological targets

Caughey

2016

European Journal of Pharmacology

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128

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Mast cells are rich in proteases, which are the major proteins of intracellular granules and are released with histamine and heparin by activated cells. Most of these proteases are active in the granule as well outside of the mast cell when secreted, and can cleave targets near degranulating mast cells and in adjoining tissue compartments. Some proteases released from mast cells reach the bloodstream and may have far-reaching actions. In terms of relative amounts, the major mast cell proteases include the tryptases, chymases, cathepsin G, carboxypeptidase A3, dipeptidylpeptidase I/cathepsin C, and cathepsins L and S. Some mast cells also produce granzyme B, plasminogen activators, and matrix metalloproteinases. Tryptases and chymases are almost entirely mast cell-specific, whereas other proteases, such as cathepsins G, C, and L are expressed by a variety of inflammatory cells. Carboxypeptidase A3 expression is a property shared by basophils and mast cells. Other proteases, such as mastins, are largely basophil-specific, although human basophils are protease-deficient compared with their murine counterparts. The major classes of mast cell proteases have been targeted for development of therapeutic inhibitors. Also, a human β-tryptase has been proposed as a potential drug itself, to inactivate of snake venins. Diseases linked to mast cell proteases include allergic diseases, such as asthma, eczema, and anaphylaxis, but also include non-allergic diseases such inflammatory bowel disease, autoimmune arthritis, atherosclerosis, aortic aneurysms, hypertension, myocardial infarction, heart failure, pulmonary hypertension and scarring diseases of lungs and other organs. In some cases, studies performed in mouse models suggest protective or homeostatic roles for specific proteases (or groups of proteases) in infections by bacteria, worms and other parasites, and even in allergic inflammation. At the same time, a clearer picture has emerged of differences in the properties and patterns of expression of proteases expressed in human mast cell subsets, and in humans versus other mammals. These considerations are influencing prioritization of specific protease targets for therapeutic inhibition, as well as options of pre-clinical models, disease indications, and choice of topical versus systemic routes of inhibitor administration.

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Mutational Tail Loss Is an Evolutionary Mechanism for Liberating Marapsins and Other Type I Serine Proteases from Transmembrane Anchors

Cited by 5 publications

References 42 publications

The testis-specific serine proteases PRSS44, PRSS46, and PRSS54 are dispensable for male mouse fertility†

The testis-specific serine proteases PRSS44, PRSS46, and PRSS54 are dispensable for male mouse fertility†

Temporary serine protease inhibition and the role of SPINK2 in human bone marrow

Mast cell proteases as pharmacological targets

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