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. 2017 Feb 14;114(7):E1128-E1137. doi: 10.1073/pnas.1616783114. Epub 2017 Feb 1.


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, GSDMB gene amplification and protein overexpression indicate a poor response to HER2-targeted therapy. Genome-wide association studies revealed a correlation between GSDMB 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 88DNVD91 within the N-terminal domain. Selective sulfatide binding may indicate possible function for GSDMB in the cellular sulfatide transport.

Keywords: GSDMB; X-ray crystallography; complex trait inflammatory disease; disease risk polymorphism; lipid binding.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Asthma / genetics*
  • Cardiolipins / metabolism
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Caspases / metabolism
  • Crystallography, X-Ray
  • Humans
  • Immobilized Proteins / metabolism
  • Inflammatory Bowel Diseases / genetics*
  • Liposomes
  • Membranes, Artificial
  • Models, Molecular
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Phosphatidylinositols / metabolism*
  • Polymorphism, Single Nucleotide*
  • Protein Binding
  • Protein Conformation
  • Protein Isoforms / metabolism
  • Recombinant Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship


  • Cardiolipins
  • Carrier Proteins
  • GSDMB protein, human
  • Immobilized Proteins
  • Liposomes
  • Membranes, Artificial
  • Neoplasm Proteins
  • Phosphatidylinositols
  • Protein Isoforms
  • Recombinant Proteins
  • Caspases

Associated data

  • PDB/5TIB
  • PDB/5TJ2
  • PDB/5TJ4