5TJ4

Gasdermin-B C-terminal domain containing the polymorphism residues Gly299:Pro306 fused to maltose binding protein

Summary for 5TJ4

• Entry DOI: 10.2210/pdb5tj4/pdb
• Related: 5TIB 5TJ2
• Related PRD ID: PRD_900001
• Descriptor: Sugar ABC transporter substrate-binding protein,Gasdermin-B fusion protein, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, SODIUM ION (3 entities in total)
• Functional Keywords: alpha helices, fusion protein, c-terminal domain, 1 snp, ligand binding protein
• Biological source: Escherichia coli, Homo sapiens (Human)
• Total number of polymer chains: 10
• Total formula weight: 617174.22

Authors

Chao, L.K.,Herzberg, O. (deposition date: 2016-10-03, release date: 2017-02-01, Last modification date: 2023-10-04)

Primary citation

Chao, K.L.,Kulakova, L.,Herzberg, O.
Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein.
Proc. Natl. Acad. Sci. U.S.A., 114:E1128-E1137, 2017

PubMed Abstract: The exact function of human gasdermin-B (GSDMB), which regulates differentiation and growth of epithelial cells, is yet to be elucidated. In human epidermal growth factor receptor 2 (HER2)-positive breast cancer, gene amplification and protein overexpression indicate a poor response to HER2-targeted therapy. Genome-wide association studies revealed a correlation between SNPs and an increased susceptibility to Crohn's disease, ulcerative colitis, and asthma. The N- and C-terminal domains of all gasdermins possess lipid-binding and regulatory activities, respectively. Inflammatory caspases cleave gasdermin-D in the interdomain linker but not GSDMB. The cleaved N-terminal domain binds phosphoinositides and cardiolipin, forms membrane-disrupting pores, and executes pyroptosis. We show that both full-length GSDMB and the N-terminal domain bind to nitrocellulose membranes immobilized with phosphoinositides or sulfatide, but not with cardiolipin. In addition, the GSDMB N-terminal domain binds liposomes containing sulfatide. The crystal structure of the GSDMB C-terminal domain reveals the structural impact of the amino acids encoded by SNPs that are linked to asthma and inflammatory bowel disease (IBD). A loop that carries the polymorphism amino acids corresponding to healthy individuals (Gly299:Pro306) exhibits high conformational flexibility, whereas the loop carrying amino acids found in individuals with increased disease risk (Arg299:Ser306) exhibits a well-defined conformation and higher positive surface charge. Apoptotic executioner caspase-3, -6, and -7, but not the inflammatory caspases, cleave GSDMB at DNVD within the N-terminal domain. Selective sulfatide binding may indicate possible function for GSDMB in the cellular sulfatide transport.

PubMed: 28154144
DOI: 10.1073/pnas.1616783114

Experimental method

X-RAY DIFFRACTION (3.5 Å)