A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junctions to Promote α-Toxin Cytotoxicity

Cell Rep. 2018 Nov 20;25(8):2132-2147.e7. doi: 10.1016/j.celrep.2018.10.088.


We previously identified PLEKHA7 and other junctional proteins as host factors mediating death by S. aureus α-toxin, but the mechanism through which junctions promote toxicity was unclear. Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. ADAM10 is locked at junctions through binding of its cytoplasmic C terminus to afadin. Junctionally clustered ADAM10 supports the efficient formation of stable toxin pores. Instead, disruption of the PLEKHA7-PDZD11 complex inhibits ADAM10 and toxin junctional clustering. This promotes toxin pore removal from the cell surface through an actin- and macropinocytosis-dependent process, resulting in cell recovery from initial injury and survival. These results uncover a dock-and-lock molecular mechanism to target ADAM10 to junctions and provide a paradigm for how junctions regulate transmembrane receptors through their clustering.

Keywords: ADAM10; Afadin; PDZD11; PLEKHA7; Staphylococcus auereus α-toxin; Tetraspanin; cell junctions; cell-death; epithelium; macropinocytosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM10 Protein / metabolism*
  • Bacterial Toxins / toxicity*
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism
  • Cell Death / drug effects
  • Cell Line
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • Hemolysin Proteins / toxicity*
  • Humans
  • Intercellular Junctions / drug effects
  • Intercellular Junctions / metabolism*
  • Microfilament Proteins / metabolism
  • Pinocytosis / drug effects
  • Protein Binding
  • Protein Domains
  • Protein Structure, Secondary
  • Tetraspanins / metabolism


  • Bacterial Toxins
  • Carrier Proteins
  • Hemolysin Proteins
  • Microfilament Proteins
  • PLEKHA7 protein, human
  • TSPAN33 protein, human
  • Tetraspanins
  • afadin
  • staphylococcal alpha-toxin
  • ADAM10 Protein