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Dive into the research topics where Charles B. Shoemaker is active.

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Featured researches published by Charles B. Shoemaker.


Nature | 1998

Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family

Luca Mastroberardino; Benjamin Spindler; Rahel Pfeiffer; Patrick J. Skelly; Jan Loffing; Charles B. Shoemaker; François Verrey

Amino-acid transport across cellular plasma membranes depends on several parallel-functioning (co-)transporters and exchangers. The widespread transport system L accounts for a sodium-independent exchange of large, neutral amino acids, whereas the system y+L exchanges positively charged amino acids and/or neutral amino acids together with sodium,. The molecular nature of these transporters remains unknown, although expression of the human cell-surface glycoprotein 4F2 heavy chain (h4F2hc; CD98 in the mouse), is known to induce low levels of L- and/or y+L-type transport. This glycoprotein is found in activated lymphocytes, together with an uncharacterized, disulphide-linked lipophilic light chain with an apparent relative molecular mass of 40,000 (Mr 40K),. Here we identify the permease-related protein E16 (ref. 12) as the first light chain of h4F2hc and show that the resulting heterodimeric complex mediates L-type amino-acid transport. The homologous protein from Schistosoma mansoni, SPRM1, also associates covalently with coexpressed h4F2hc glycoprotein, although it induces amino-acid transport of different substrate specificity. The coexpression of h4F2hc is required for surface expression of these permease-related light chains, which belong to a new family of amino-acid transporters that form heterodimers with cell-surface glycoproteins.


Journal of Immunology | 2001

Sandfly Maxadilan Exacerbates Infection with Leishmania major and Vaccinating Against It Protects Against L. major Infection

Robin V. Morris; Charles B. Shoemaker; John R. David; Gregory C. Lanzaro; Richard G. Titus

Bloodfeeding arthropods transmit many of the world’s most serious infectious diseases. Leishmania are transmitted to their mammalian hosts when an infected sandfly probes in the skin for a bloodmeal and injects the parasite mixed with its saliva. Arthropod saliva contains molecules that affect blood flow and modulate the immune response of the host. Indeed, sandfly saliva markedly enhances the infectivity of L. major for its host. If the salivary molecule(s) responsible for this phenomenon was identified, it might be possible to vaccinate the host against this molecule and thereby protect the host against infection with Leishmania. Such an approach represents a novel means of controlling arthropod-borne disease transmission. Here, we report that a single molecule, maxadilan, in sandfly saliva can exacerbate infection with L. major to the same degree as whole saliva, and that vaccinating against maxadilan protects mice against infection with L. major.


Science | 2012

Botulinum neurotoxin is shielded by NTNHA in an interlocked complex.

Shenyan Gu; Sophie Rumpel; Jie Zhou; Jasmin Strotmeier; Hans Bigalke; Kay Perry; Charles B. Shoemaker; Andreas Rummel; Rongsheng Jin

Piercing Botulinums Defense Botulinum neurotoxins (BoNTs) are poisons that cause muscle paralysis. In the acidic intestine, ingested BoNTs are protected within a progenitor toxin complex. The toxins are released on absorption into the neutral bloodstream. Gu et al. (p. 977; see the Perspective by Adler) present the structure of a minimally functional progenitor toxin complex—BoNT in complex with a nontoxic, nonhemagglutinin protein at 2.7 angstrom resolution. The structure, together with biochemical studies, showed how complex assembly is regulated by pH and may be useful in guiding the development of delivery vehicles for oral administration of biologics and in the design of inhibitors for oral BoNT poisoning. Structural and biochemical studies show how a bacterial toxin protects itself against digestion in the gut. Botulinum neurotoxins (BoNTs) are highly poisonous substances that are also effective medicines. Accidental BoNT poisoning often occurs through ingestion of Clostridium botulinum–contaminated food. Here, we present the crystal structure of a BoNT in complex with a clostridial nontoxic nonhemagglutinin (NTNHA) protein at 2.7 angstroms. Biochemical and functional studies show that NTNHA provides large and multivalent binding interfaces to protect BoNT from gastrointestinal degradation. Moreover, the structure highlights key residues in BoNT that regulate complex assembly in a pH-dependent manner. Collectively, our findings define the molecular mechanisms by which NTNHA shields BoNT in the hostile gastrointestinal environment and releases it upon entry into the circulation. These results will assist in the design of small molecules for inhibiting oral BoNT intoxication and of delivery vehicles for oral administration of biologics.


FEBS Letters | 1998

Functional heterodimeric amino acid transporters lacking cysteine residues involved in disulfide bond

Rahel Pfeiffer; Benjamin Spindler; Jan Loffing; Patrick J. Skelly; Charles B. Shoemaker; François Verrey

The protein mediating system L amino acid transport, AmAT‐L, is a disulfide‐linked heterodimer of a permease‐related light chain (AmAT‐L‐lc) and the type II glycoprotein 4F2hc/CD98. The Schistosoma mansoni protein SPRM1 also heterodimerizes with h4F2hc, inducing amino acid transport with different specificity. In this study, we show that the disulfide bond is formed by heavy chain C109 with a Cys residue located in the second putative extracellular loop of the multi‐transmembrane domain light chain (C164 and C137 for XAmAT‐L‐lc and SPRM1, respectively). The non‐covalent interaction of Cys‐mutant subunits is not sufficient to allow coimmunoprecipitation, but cell surface expression of the light chains is maintained to a large extent. The non‐covalently linked transporters display the same transport characteristics as disulfide bound heterodimers, but the maximal transport rates are reduced by 30–80%.


Journal of Biological Chemistry | 1998

A Divergent Member of the Transforming Growth Factor β Receptor Family from Schistosoma mansoni Is Expressed on the Parasite Surface Membrane

Stephen J. Davies; Charles B. Shoemaker; Edward J. Pearce

To optimize reproductive success under the limitations determined by conditions within an individual host, parasitic helminths have evolved mechanisms that allow them to detect and respond to host factors such as species, age, sex, reproductive condition, and immune status. Using the model helminthSchistosoma mansoni, we have explored the possibility that parasitic helminths express signal-transducing receptor molecules on their surfaces. Here, we present the identification of a schistosome member of the transforming growth factor β receptor family of cell-surface receptors, the first member of this family to be identified in a platyhelminth. The putative protein kinase domain of the schistosome receptor displays up to 58% amino acid identity to kinase domains of other type I receptor serine-threonine kinases, and contains a potential “GS domain,” suggesting it is a divergent member of the type I receptor subfamily. This receptor is expressed on the surface of the parasite’s syncytial tegument and expression of receptor messenger RNA and protein is up-regulated following infection of the mammalian host. The receptor protein can be isolated in a phosphorylated form from adult parasites, which together with its surface location, suggests that it functions in transducing signals across the parasite surface membrane.


Shock | 2005

CALCITONIN GENE-RELATED PEPTIDE INHIBITS LOCAL ACUTE INFLAMMATION AND PROTECTS MICE AGAINST LETHAL ENDOTOXEMIA

Rachel N. Gomes; Hugo C. Castro-Faria-Neto; Patricia T. Bozza; Milena B. P. Soares; Charles B. Shoemaker; John R. David; Marcelo T. Bozza

Calcitonin gene-related peptide (CGRP), a potent vasodilatory peptide present in central and peripheral neurons, is released at inflammatory sites and inhibits several macrophage, dendritic cell, and lymphocyte functions. In the present study, we investigated the role of CGRP in models of local and systemic acute inflammation and on macrophage activation induced by lipopolysaccharide (LPS). Intraperitoneal pretreatment with synthetic CGRP reduces in approximately 50% the number of neutrophils in the blood and into the peritoneal cavity 4 h after LPS injection. CGRP failed to inhibit neutrophil recruitment induced by the direct chemoattractant platelet-activating factor, whereas it significantly inhibited LPS-induced KC generation, suggesting that the effect of CGRP on neutrophil recruitment is indirect, acting on chemokine production by resident cells. Pretreatment of mice with 1 μg of CGRP protects against a lethal dose of LPS. The CGRP-induced protection is receptor mediated because it is completely reverted by the CGRP receptor antagonist, CGRP 8-37. The protective effect of CGRP correlates with an inhibition of TNF-α and an induction of IL-6 and IL-10 in mice sera 90 min after LPS challenge. Finally, CGRP significantly inhibits LPS-induced TNF-α released from mouse peritoneal macrophages. These results suggest that activation of the CGRP receptor on macrophages during acute inflammation could be part of the negative feedback mechanism controlling the extension of acute inflammatory responses.


Molecular and Biochemical Parasitology | 1992

Alternative splicing of the Schistosoma mansoni gene encoding a homologue of epidermal growth factor receptor

Charles B. Shoemaker; Abraham Landa; Mitermayer G. Reis; Lincoln D. Stein

The complete coding DNA for a Schistosoma mansoni homologue of the epidermal growth factor receptor (SER) was characterized from cDNA clones obtained by homology to the tyrosine kinase domain of erbB. The DNA sequence predicts a 200-kDa translation product that contains a secretory leader, a cysteine-rich extracellular domain, a hydrophobic transmembrane sequence, and an intracellular tyrosine kinase domain. The SER transcript is present in cercariae and adult schistosomes. In addition to SER transcripts, schistosomes produce at least 3 variant transcripts encoding truncated SER products that include the secretory leader and a small portion of the extracellular domain followed by short sequences of unrelated, C-terminal amino acids. Based on these sequences, 2 of the variant mRNAs (class 2 and 5) appear to encode soluble, secreted proteins while one (class 4) encodes an SER variant protein with a hydrophobic C-terminus that may serve as a membrane anchor. Class 2 SER variant transcripts are present at levels comparable to SER transcripts in adult worms but are not detected in cercariae. Class 4 and 5 SER variant transcripts are also found within adult worms but at lower levels. Genomic cloning and characterization demonstrate that the variant SER transcripts arise through alternative splicing of the SER gene.


Molecular and Biochemical Parasitology | 1991

Paramyosin is the Schistosoma mansoni (Trematoda) homologue of antigen B from Taenia solium (Cestoda).

Juan Pedro Laclette; Abraham Landa; Lourdes Arcos; Kaethe Willms; Alvin E. Davis; Charles B. Shoemaker

Antigen B, a major antigen of the cestode parasite Taenia solium, has been purified and a portion of amino acid sequence obtained. Paramyosin of the trematode parasite Schistosoma mansoni, an immunogenic protein that has shown promise as a vaccine candidate, has several biochemical and immunological properties in common with antigen B. A full-length cDNA clone of S. mansoni paramyosin has been obtained and the predicted translation product contains a sequence that is highly homologous to the sequence obtained for antigen B. The predicted amino acid composition and isolectric point of paramyosin are nearly identical to those established for antigen B. Recombinant S. mansoni paramyosin, expressed in Escherichia coli as a fusion protein with beta-galactosidase, was recognized by antisera against T. solium antigen B. We conclude from these results that S. mansoni paramyosin and T. solium antigen B are homologous proteins. Since S. mansoni paramyosin is thought to be a muscle protein and T. solium antigen B a secreted glycoprotein with anti-complement activity, this conclusion raises some interesting questions regarding the role of this class of proteins in the host-parasite relationship.


Proceedings of the National Academy of Sciences of the United States of America | 2010

Targeting botulinum neurotoxin persistence by the ubiquitin-proteasome system

Yien Che Tsai; Rhyan Maditz; Chueh-Ling Kuo; Paul S. Fishman; Charles B. Shoemaker; George A. Oyler; Allan M. Weissman

Botulinum neurotoxins (BoNTs) are the most potent natural toxins known. The effects of BoNT serotype A (BoNT/A) can last several months, whereas the effects of BoNT serotype E (BoNT/E), which shares the same synaptic target, synaptosomal-associated protein 25 (SNAP25), last only several weeks. The long-lasting effects or persistence of BoNT/A, although desirable for therapeutic applications, presents a challenge for medical treatment of BoNT intoxication. Although the mechanisms for BoNT toxicity are well known, little is known about the mechanisms that govern the persistence of the toxins. We show that the recombinant catalytic light chain (LC) of BoNT/E is ubiquitylated and rapidly degraded in cells. In contrast, BoNT/A LC is considerably more stable. Differential susceptibility of the catalytic LCs to ubiquitin-dependent proteolysis therefore might explain the differential persistence of BoNT serotypes. In this regard we show that TRAF2, a RING finger protein implicated in ubiquitylation, selectively associates with BoNT/E LC and promotes its proteasomal degradation. Given these data, we asked whether BoNT/A LC could be targeted for rapid proteasomal degradation by redirecting it to characterized ubiquitin ligase domains. We describe chimeric SNAP25-based ubiquitin ligases that target BoNT/A LC for degradation, reducing its duration in a cellular model for toxin persistence.


PLOS ONE | 2012

A Novel Strategy for Development of Recombinant Antitoxin Therapeutics Tested in a Mouse Botulism Model

Jean Mukherjee; Jacqueline M. Tremblay; Clinton E. Leysath; Kwasi Ofori; Karen Baldwin; Xiaochuan Feng; Daniela Bedenice; Robert P. Webb; Patrick M. Wright; Leonard A. Smith; Saul Tzipori; Charles B. Shoemaker

Antitoxins are needed that can be produced economically with improved safety and shelf life compared to conventional antisera-based therapeutics. Here we report a practical strategy for development of simple antitoxin therapeutics with substantial advantages over currently available treatments. The therapeutic strategy employs a single recombinant ‘targeting agent’ that binds a toxin at two unique sites and a ‘clearing Ab’ that binds two epitopes present on each targeting agent. Co-administration of the targeting agent and the clearing Ab results in decoration of the toxin with up to four Abs to promote accelerated clearance. The therapeutic strategy was applied to two Botulinum neurotoxin (BoNT) serotypes and protected mice from lethality in two different intoxication models with an efficacy equivalent to conventional antitoxin serum. Targeting agents were a single recombinant protein consisting of a heterodimer of two camelid anti-BoNT heavy-chain-only Ab VH (VHH) binding domains and two E-tag epitopes. The clearing mAb was an anti-E-tag mAb. By comparing the in vivo efficacy of treatments that employed neutralizing vs. non-neutralizing agents or the presence vs. absence of clearing Ab permitted unprecedented insight into the roles of toxin neutralization and clearance in antitoxin efficacy. Surprisingly, when a post-intoxication treatment model was used, a toxin-neutralizing heterodimer agent fully protected mice from intoxication even in the absence of clearing Ab. Thus a single, easy-to-produce recombinant protein was as efficacious as polyclonal antiserum in a clinically-relevant mouse model of botulism. This strategy should have widespread application in antitoxin development and other therapies in which neutralization and/or accelerated clearance of a serum biomolecule can offer therapeutic benefit.

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Nicholas J. Mantis

New York State Department of Health

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David J. Vance

New York State Department of Health

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