Dataset Information

Structure and Function of FS50, a salivary protein from the flea Xenopsylla cheopis that blocks the sodium channel NaV1.5.

ABSTRACT: Naturally occurring toxins have been invaluable tools for the study of structural and functional relationships of voltage-gated sodium channels (VGSC). Few studies have been made of potential channel-modulating substances from blood-feeding arthropods. He we describe the characterization FS50, a salivary protein from the flea, Xenopsylla cheopis, that exhibits an inhibitory activity against the NaV1.5 channel with an IC50 of 1.58??M. The pore-blocking mechanism of this toxin is evident from the kinetics of activation and inactivation suggesting that FS50 does not interfere with the voltage sensor of NaV1.5. FS50 exhibits high specificity for NaV1.5, since 10??M FS50 had no discernable effect on voltage-gated Na+, K+ and Ca2+ channels in rat dorsal root ganglia or VGSC forms individually expressed in HEK 293T cells. Furthermore, intravenous injection of FS50 into rats and monkeys elicited recovery from arrhythmia induced by BaCl2, as would be expected from a blockade of NaV1.5. The crystal structure of FS50 revealed a ???? domain similar to that of scorpion ? toxin and a small N-terminal ??? domain. Site-directed mutagenesis experiments have implicated a basic surface including the side chains of Arg 6, His 11 and Lys 32 as potentially important in the FS50 NaV1.5 interaction.

SUBMITTER: Xu X

PROVIDER: S-EPMC5098211 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structure and Function of FS50, a salivary protein from the flea Xenopsylla cheopis that blocks the sodium channel NaV1.5.

Xu Xueqing X Zhang Bei B Yang Shilong S An Su S Ribeiro José M C JM Andersen John F JF

Scientific reports 20161107

Naturally occurring toxins have been invaluable tools for the study of structural and functional relationships of voltage-gated sodium channels (VGSC). Few studies have been made of potential channel-modulating substances from blood-feeding arthropods. He we describe the characterization FS50, a salivary protein from the flea, Xenopsylla cheopis, that exhibits an inhibitory activity against the NaV1.5 channel with an IC50 of 1.58 μM. The pore-blocking mechanism of this toxi ...[more]

PMID: 27819327

Similar Datasets

Project description:Over the last 20 years, advances in sequencing technologies paired with biochemical and structural studies have shed light on the unique pharmacological arsenal produced by the salivary glands of hematophagous arthropods that can target host hemostasis and immune response, favoring blood acquisition and, in several cases, enhancing pathogen transmission. Here we provide a deeper insight into Xenopsylla cheopis salivary gland contents pairing transcriptomic and proteomic approaches. Sequencing of 99 pairs of salivary glands from adult female X. cheopis yielded a total of 7432 coding sequences functionally classified into 25 classes, of which the secreted protein class was the largest. The translated transcripts also served as a reference database for the proteomic study, which identified peptides from 610 different proteins. Both approaches revealed that the acid phosphatase family is the most abundant salivary protein group from X. cheopis. Additionally, we report here novel sequences similar to the FS-H family, apyrases, odorant and hormone-binding proteins, antigen 5-like proteins, adenosine deaminases, peptidase inhibitors from different subfamilies, proteins rich in Glu, Gly, and Pro residues, and several potential secreted proteins with unknown function. SIGNIFICANCE: The rat flea X. cheopis is the main vector of Yersinia pestis, the etiological agent of the bubonic plague responsible for three major pandemics that marked human history and remains a burden to human health. In addition to Y. pestis fleas can also transmit other medically relevant pathogens including Rickettsia spp. and Bartonella spp. The studies of salivary proteins from other hematophagous vectors highlighted the importance of such molecules for blood acquisition and pathogen transmission. However, despite the historical and clinical importance of X. cheopis little is known regarding their salivary gland contents and potential activities. Here we provide a comprehensive analysis of X. cheopis salivary composition using next generation sequencing methods paired with LC-MS/MS analysis, revealing its unique composition compared to the sialomes of other blood-feeding arthropods, and highlighting the different pathways taken during the evolution of salivary gland concoctions. In the absence of the X. cheopis genome sequence, this work serves as an extended reference for the identification of potential pharmacological proteins and peptides present in flea saliva.

Dataset Information

Structure and Function of FS50, a salivary protein from the flea Xenopsylla cheopis that blocks the sodium channel NaV1.5.

Publications

Structure and Function of FS50, a salivary protein from the flea Xenopsylla cheopis that blocks the sodium channel Na<sub>V</sub>1.5.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets