Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein.
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,GSDMBgene amplification and protein overexpression indicate a poor response to HER2-targeted therapy. Genome-wide association studies revealed a correlation betweenGSDMBSNPs 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 at88DNVD91within the N-terminal domain. Selective sulfatide binding may indicate possible function for GSDMB in the cellular sulfatide transport.
Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850.
Kinlin L
KL
Chao
Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850.
Liudmila
L
Kulakova
Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850; osnat@umd.edu.|Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742.
Osnat
O
Herzberg
D000595:Amino Acid Sequence; D001249:Asthma / Q000235:genetics*; D002308:Cardiolipins / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D055767:Immobilized Proteins / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D008081:Liposomes; D008567:Membranes, Artificial; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D000094524:Gasdermins
D002308:Cardiolipins; D002352:Carrier Proteins; D020169:Caspases; D055767:Immobilized Proteins; D008081:Liposomes; D008567:Membranes, Artificial; D009363:Neoplasm Proteins; D010716:Phosphatidylinositols; D020033:Protein Isoforms; D011994:Recombinant Proteins; C527978:GSDMB protein, human; D000094524:Gasdermins
GSDMB; X-ray crystallography; complex trait inflammatory disease; disease risk polymorphism; lipid binding