Structure of the human receptor tyrosine kinase met in complex with the Listeria invasion protein InlB.
The tyrosine kinase Met, the product of the c-met proto-oncogene and the receptor for hepatocyte growth factor/scatter factor (HGF/SF), mediates signals critical for cell survival and migration. The human pathogen Listeria monocytogenes exploits Met signaling for invasion of host cells via its surface protein InlB. We present the crystal structure of the complex between a large fragment of the human Met ectodomain and the Met-binding domain of InlB. The concave face of the InlB leucine-rich repeat region interacts tightly with the first immunoglobulin-like domain of the Met stalk, a domain which does not bind HGF/SF. A second contact between InlB and the Met Sema domain locks the otherwise flexible receptor in a rigid, signaling competent conformation. Full Met activation requires the additional C-terminal domains of InlB which induce heparin-mediated receptor clustering and potent signaling. Thus, although it elicits a similar cellular response, InlB is not a structural mimic of HGF/SF.
Division of Structural Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, D-38124 Braunschweig, Germany.
Hartmut H
HH
Niemann
Volker
V
Jäger
P Jonathan G
PJ
Butler
Joop
J
van den Heuvel
Sabine
S
Schmidt
Davide
D
Ferraris
Ermanno
E
Gherardi
Dirk W
DW
Heinz
D001426:Bacterial Proteins / Q000737:chemistry*; D001665:Binding Sites; D006493:Heparin / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D000090263:Leucine-Rich Repeat Proteins; D008089:Listeria monocytogenes / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry*; D008954:Models, Biological; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry*
D001426:Bacterial Proteins; D000090263:Leucine-Rich Repeat Proteins; C000715470:MAS1 protein, human; D008565:Membrane Proteins; D011506:Proteins; D000090063:Proto-Oncogene Mas; C095768:inlB protein, Listeria monocytogenes; D017228:Hepatocyte Growth Factor; D006493:Heparin; D019859:Proto-Oncogene Proteins c-met