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A family of orthologous proteins from centipede venoms inhibit the hKir6.2 channel.

ABSTRACT: Inhibitors targeting ion channels are useful tools for studying their functions. Given the selectivity of any inhibitor for a channel is relative, more than one inhibitor of different affinities may be used to help identify the channel in a biological preparation. Here, we describe a family of small proteins in centipede venoms that inhibit the pore (hKir6.2) of a human ATP-sensitive K+ channel (hKATP). While the traditional peptide-sequencing service gradually vanishes from academic institutions, we tried to identify the sequences of inhibitory proteins purified from venoms by searching the sequences of the corresponding transcriptomes, a search guided by the key features of a known hKir6.2 inhibitor (SpTx1). The candidate sequences were cross-checked against the masses of purified proteins, and validated by testing the activity of recombinant proteins against hKir6.2. The four identified proteins (SsdTx1-3 and SsTx) inhibit hKATP channels with a Kd of <300?nM, compared to 15?nM for SpTx1. SsTx has previously been discovered to block human voltage-gated KCNQ K+ channels with a 2.5??M?Kd. Given that SsTx inhibits hKir6.2 with >10-fold lower Kd than it inhibits hKCNQ, SsTx may not be suitable for probing KCNQ channels in a biological preparation that also contains more-SsTx-sensitive KATP channels.

SUBMITTER: Ramu Y

PROVIDER: S-EPMC6773964 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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A family of orthologous proteins from centipede venoms inhibit the hKir6.2 channel.

Ramu Yajamana Y Lu Zhe Z

Scientific reports 20191001 1

Inhibitors targeting ion channels are useful tools for studying their functions. Given the selectivity of any inhibitor for a channel is relative, more than one inhibitor of different affinities may be used to help identify the channel in a biological preparation. Here, we describe a family of small proteins in centipede venoms that inhibit the pore (hKir6.2) of a human ATP-sensitive K<sup>+</sup> channel (hK<sub>ATP</sub>). While the traditional peptide-sequencing service gradually vanishes fro ...[more]

PMID: 31575961

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Project description:While many studies have shown that extracellular proteins evolve rapidly, how selection acts on them remains poorly understood. We used snake venoms to understand the interaction between ecology, expression level, and evolutionary rate in secreted protein systems. Venomous snakes employ well-integrated systems of proteins and organic constituents to immobilize prey. Venoms are generally optimized to subdue preferred prey more effectively than non-prey, and many venom protein families manifest positive selection and rapid gene family diversification. Although previous studies have illuminated how individual venom protein families evolve, how selection acts on venoms as integrated systems, is unknown.Using next-generation transcriptome sequencing and mass spectrometry, we examined microevolution in two pitvipers, allopatrically separated for at least 1.6 million years, and their hybrids. Transcriptomes of parental species had generally similar compositions in regard to protein families, but for a given protein family, the homologs present and concentrations thereof sometimes differed dramatically. For instance, a phospholipase A2 transcript comprising 73.4 % of the Protobothrops elegans transcriptome, was barely present in the P. flavoviridis transcriptome (<0.05 %). Hybrids produced most proteins found in both parental venoms. Protein evolutionary rates were positively correlated with transcriptomic and proteomic abundances, and the most abundant proteins showed positive selection. This pattern holds with the addition of four other published crotaline transcriptomes, from two more genera, and also for the recently published king cobra genome, suggesting that rapid evolution of abundant proteins may be generally true for snake venoms. Looking more broadly at Protobothrops, we show that rapid evolution of the most abundant components is due to positive selection, suggesting an interplay between abundance and adaptation.Given log-scale differences in toxin abundance, which are likely correlated with biosynthetic costs, we hypothesize that as a result of natural selection, snakes optimize return on energetic investment by producing more of venom proteins that increase their fitness. Natural selection then acts on the additive genetic variance of these components, in proportion to their contributions to overall fitness. Adaptive evolution of venoms may occur most rapidly through changes in expression levels that alter fitness contributions, and thus the strength of selection acting on specific secretome components.

Dataset Information

A family of orthologous proteins from centipede venoms inhibit the hKir6.2 channel.

Publications

A family of orthologous proteins from centipede venoms inhibit the hKir6.2 channel.

Similar Datasets

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