Stonefish toxin defines an ancient branch of the perforin-like superfamily

Andrew M Ellisdon, Cyril F Reboul, Santosh Panjikar, Kitmun Huynh, Christine A Oellig, Kelly L Winter, Michelle A Dunstone, Wayne C Hodgson, Jamie E Seymour, Peter K Dearden, Rodney K Tweten, James C Whisstock, Sheena McGowan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The lethal factor in stonefish venom is stonustoxin (SNTX), a heterodimeric cytolytic protein that induces cardiovascular collapse in humans and native predators. Here, using X-ray crystallography, we make the unexpected finding that SNTX is a pore-forming member of an ancient branch of the Membrane Attack Complex-Perforin/Cholesterol-Dependent Cytolysin (MACPF/CDC) superfamily. SNTX comprises two homologous subunits (alpha and beta), each of which comprises an N-terminal pore-forming MACPF/CDC domain, a central focal adhesion-targeting domain, a thioredoxin domain, and a C-terminal tripartite motif family-like PRY SPla and the RYanodine Receptor immune recognition domain. Crucially, the structure reveals that the two MACPF domains are in complex with one another and arranged into a stable early prepore-like assembly. These data provide long sought after near-atomic resolution insights into how MACPF/CDC proteins assemble into prepores on the surface of membranes. Furthermore, our analyses reveal that SNTX-like MACPF/CDCs are distributed throughout eukaryotic life and play a broader, possibly immune-related function outside venom.
Original languageEnglish
Pages (from-to)15360 - 15365
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume112
Issue number50
DOIs
Publication statusPublished - 2015

Cite this

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title = "Stonefish toxin defines an ancient branch of the perforin-like superfamily",
abstract = "The lethal factor in stonefish venom is stonustoxin (SNTX), a heterodimeric cytolytic protein that induces cardiovascular collapse in humans and native predators. Here, using X-ray crystallography, we make the unexpected finding that SNTX is a pore-forming member of an ancient branch of the Membrane Attack Complex-Perforin/Cholesterol-Dependent Cytolysin (MACPF/CDC) superfamily. SNTX comprises two homologous subunits (alpha and beta), each of which comprises an N-terminal pore-forming MACPF/CDC domain, a central focal adhesion-targeting domain, a thioredoxin domain, and a C-terminal tripartite motif family-like PRY SPla and the RYanodine Receptor immune recognition domain. Crucially, the structure reveals that the two MACPF domains are in complex with one another and arranged into a stable early prepore-like assembly. These data provide long sought after near-atomic resolution insights into how MACPF/CDC proteins assemble into prepores on the surface of membranes. Furthermore, our analyses reveal that SNTX-like MACPF/CDCs are distributed throughout eukaryotic life and play a broader, possibly immune-related function outside venom.",
author = "Ellisdon, {Andrew M} and Reboul, {Cyril F} and Santosh Panjikar and Kitmun Huynh and Oellig, {Christine A} and Winter, {Kelly L} and Dunstone, {Michelle A} and Hodgson, {Wayne C} and Seymour, {Jamie E} and Dearden, {Peter K} and Tweten, {Rodney K} and Whisstock, {James C} and Sheena McGowan",
year = "2015",
doi = "10.1073/pnas.1507622112",
language = "English",
volume = "112",
pages = "15360 -- 15365",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "50",

}

Stonefish toxin defines an ancient branch of the perforin-like superfamily. / Ellisdon, Andrew M; Reboul, Cyril F; Panjikar, Santosh; Huynh, Kitmun; Oellig, Christine A; Winter, Kelly L; Dunstone, Michelle A; Hodgson, Wayne C; Seymour, Jamie E; Dearden, Peter K; Tweten, Rodney K; Whisstock, James C; McGowan, Sheena.

In: Proceedings of the National Academy of Sciences, Vol. 112, No. 50, 2015, p. 15360 - 15365.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Stonefish toxin defines an ancient branch of the perforin-like superfamily

AU - Ellisdon, Andrew M

AU - Reboul, Cyril F

AU - Panjikar, Santosh

AU - Huynh, Kitmun

AU - Oellig, Christine A

AU - Winter, Kelly L

AU - Dunstone, Michelle A

AU - Hodgson, Wayne C

AU - Seymour, Jamie E

AU - Dearden, Peter K

AU - Tweten, Rodney K

AU - Whisstock, James C

AU - McGowan, Sheena

PY - 2015

Y1 - 2015

N2 - The lethal factor in stonefish venom is stonustoxin (SNTX), a heterodimeric cytolytic protein that induces cardiovascular collapse in humans and native predators. Here, using X-ray crystallography, we make the unexpected finding that SNTX is a pore-forming member of an ancient branch of the Membrane Attack Complex-Perforin/Cholesterol-Dependent Cytolysin (MACPF/CDC) superfamily. SNTX comprises two homologous subunits (alpha and beta), each of which comprises an N-terminal pore-forming MACPF/CDC domain, a central focal adhesion-targeting domain, a thioredoxin domain, and a C-terminal tripartite motif family-like PRY SPla and the RYanodine Receptor immune recognition domain. Crucially, the structure reveals that the two MACPF domains are in complex with one another and arranged into a stable early prepore-like assembly. These data provide long sought after near-atomic resolution insights into how MACPF/CDC proteins assemble into prepores on the surface of membranes. Furthermore, our analyses reveal that SNTX-like MACPF/CDCs are distributed throughout eukaryotic life and play a broader, possibly immune-related function outside venom.

AB - The lethal factor in stonefish venom is stonustoxin (SNTX), a heterodimeric cytolytic protein that induces cardiovascular collapse in humans and native predators. Here, using X-ray crystallography, we make the unexpected finding that SNTX is a pore-forming member of an ancient branch of the Membrane Attack Complex-Perforin/Cholesterol-Dependent Cytolysin (MACPF/CDC) superfamily. SNTX comprises two homologous subunits (alpha and beta), each of which comprises an N-terminal pore-forming MACPF/CDC domain, a central focal adhesion-targeting domain, a thioredoxin domain, and a C-terminal tripartite motif family-like PRY SPla and the RYanodine Receptor immune recognition domain. Crucially, the structure reveals that the two MACPF domains are in complex with one another and arranged into a stable early prepore-like assembly. These data provide long sought after near-atomic resolution insights into how MACPF/CDC proteins assemble into prepores on the surface of membranes. Furthermore, our analyses reveal that SNTX-like MACPF/CDCs are distributed throughout eukaryotic life and play a broader, possibly immune-related function outside venom.

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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