6cb8

Cryo-EM structure of the Gasdermin A3 membrane poreCryo-EM structure of the Gasdermin A3 membrane pore

6cb8, resolution 3.80Å

Structural highlights

6cb8 is a 1 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	Gsdma3, Gsdm3 (LK3 transgenic mice)
Experimental data:	Check
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[GSDA3_MOUSE] Defects in Gsdma3 are the cause of a number of alopecia phenotypes, bareskin (Bsk), defolliculated (Dfl), finnegan (Fgn) reduced coat 2 (Rco2), Rex-denuded (Re-den) and recombination induced mutation 3 (Rim3). These are dominant conditions characterized by loss of hair.^[1] ^[2] ^[3]

Function

[GSDA3_MOUSE] Upon activation, mediates pyroptosis (PubMed:26375003). May play a role in the transition from catagen to telogen at the end of hair follicle morphogenesis (PubMed:15475261).^[4] ^[5]

Publication Abstract from PubMed

Gasdermins mediate inflammatory cell death after cleavage by caspases or other, unknown enzymes. The cleaved N-terminal fragments bind to acidic membrane lipids to form pores, but the mechanism of pore formation remains unresolved. Here we present the cryo-electron microscopy structures of the 27-fold and 28-fold single-ring pores formed by the N-terminal fragment of mouse GSDMA3 (GSDMA3-NT) at 3.8 and 4.2 A resolutions, and of a double-ring pore at 4.6 A resolution. In the 27-fold pore, a 108-stranded anti-parallel beta-barrel is formed by two beta-hairpins from each subunit capped by a globular domain. We identify a positively charged helix that interacts with the acidic lipid cardiolipin. GSDMA3-NT undergoes radical conformational changes upon membrane insertion to form long, membrane-spanning beta-strands. We also observe an unexpected additional symmetric ring of GSDMA3-NT subunits that does not insert into the membrane in the double-ring pore, which may represent a pre-pore state of GSDMA3-NT. These structures provide a basis that explains the activities of several mutant gasdermins, including defective mutants that are associated with cancer.

Cryo-EM structure of the gasdermin A3 membrane pore.,Ruan J, Xia S, Liu X, Lieberman J, Wu H Nature. 2018 May;557(7703):62-67. doi: 10.1038/s41586-018-0058-6. Epub 2018 Apr, 25. PMID:29695864^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Runkel F, Marquardt A, Stoeger C, Kochmann E, Simon D, Kohnke B, Korthaus D, Wattler F, Fuchs H, Hrabe de Angelis M, Stumm G, Nehls M, Wattler S, Franz T, Augustin M. The dominant alopecia phenotypes Bareskin, Rex-denuded, and Reduced Coat 2 are caused by mutations in gasdermin 3. Genomics. 2004 Nov;84(5):824-35. PMID:15475261 doi:http://dx.doi.org/S0888-7543(04)00179-X
↑ Lunny DP, Weed E, Nolan PM, Marquardt A, Augustin M, Porter RM. Mutations in gasdermin 3 cause aberrant differentiation of the hair follicle and sebaceous gland. J Invest Dermatol. 2005 Mar;124(3):615-21. PMID:15737203 doi:http://dx.doi.org/10.1111/j.0022-202X.2005.23623.x
↑ Tanaka S, Tamura M, Aoki A, Fujii T, Komiyama H, Sagai T, Shiroishi T. A new Gsdma3 mutation affecting anagen phase of first hair cycle. Biochem Biophys Res Commun. 2007 Aug 10;359(4):902-7. Epub 2007 Jun 8. PMID:17572385 doi:http://dx.doi.org/10.1016/j.bbrc.2007.05.209
↑ Runkel F, Marquardt A, Stoeger C, Kochmann E, Simon D, Kohnke B, Korthaus D, Wattler F, Fuchs H, Hrabe de Angelis M, Stumm G, Nehls M, Wattler S, Franz T, Augustin M. The dominant alopecia phenotypes Bareskin, Rex-denuded, and Reduced Coat 2 are caused by mutations in gasdermin 3. Genomics. 2004 Nov;84(5):824-35. PMID:15475261 doi:http://dx.doi.org/S0888-7543(04)00179-X
↑ Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015 Oct 29;526(7575):660-5. doi: 10.1038/nature15514. Epub 2015 Sep 16. PMID:26375003 doi:http://dx.doi.org/10.1038/nature15514
↑ Ruan J, Xia S, Liu X, Lieberman J, Wu H. Cryo-EM structure of the gasdermin A3 membrane pore. Nature. 2018 May;557(7703):62-67. doi: 10.1038/s41586-018-0058-6. Epub 2018 Apr, 25. PMID:29695864 doi:http://dx.doi.org/10.1038/s41586-018-0058-6

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Runkel F, Marquardt A, Stoeger C, Kochmann E, Simon D, Kohnke B, Korthaus D, Wattler F, Fuchs H, Hrabe de Angelis M, Stumm G, Nehls M, Wattler S, Franz T, Augustin M. The dominant alopecia phenotypes Bareskin, Rex-denuded, and Reduced Coat 2 are caused by mutations in gasdermin 3. Genomics. 2004 Nov;84(5):824-35. PMID:15475261 doi:http://dx.doi.org/S0888-7543(04)00179-X

[2] Lunny DP, Weed E, Nolan PM, Marquardt A, Augustin M, Porter RM. Mutations in gasdermin 3 cause aberrant differentiation of the hair follicle and sebaceous gland. J Invest Dermatol. 2005 Mar;124(3):615-21. PMID:15737203 doi:http://dx.doi.org/10.1111/j.0022-202X.2005.23623.x

[3] Tanaka S, Tamura M, Aoki A, Fujii T, Komiyama H, Sagai T, Shiroishi T. A new Gsdma3 mutation affecting anagen phase of first hair cycle. Biochem Biophys Res Commun. 2007 Aug 10;359(4):902-7. Epub 2007 Jun 8. PMID:17572385 doi:http://dx.doi.org/10.1016/j.bbrc.2007.05.209

[4] Runkel F, Marquardt A, Stoeger C, Kochmann E, Simon D, Kohnke B, Korthaus D, Wattler F, Fuchs H, Hrabe de Angelis M, Stumm G, Nehls M, Wattler S, Franz T, Augustin M. The dominant alopecia phenotypes Bareskin, Rex-denuded, and Reduced Coat 2 are caused by mutations in gasdermin 3. Genomics. 2004 Nov;84(5):824-35. PMID:15475261 doi:http://dx.doi.org/S0888-7543(04)00179-X

[5] Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015 Oct 29;526(7575):660-5. doi: 10.1038/nature15514. Epub 2015 Sep 16. PMID:26375003 doi:http://dx.doi.org/10.1038/nature15514

[6] Ruan J, Xia S, Liu X, Lieberman J, Wu H. Cryo-EM structure of the gasdermin A3 membrane pore. Nature. 2018 May;557(7703):62-67. doi: 10.1038/s41586-018-0058-6. Epub 2018 Apr, 25. PMID:29695864 doi:http://dx.doi.org/10.1038/s41586-018-0058-6

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