4aw4

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Engineered variant of Listeria monocytogenes InlB internalin domain with an additional leucine rich repeat insertedEngineered variant of Listeria monocytogenes InlB internalin domain with an additional leucine rich repeat inserted

Structural highlights

4aw4 is a 3 chain structure with sequence from Listeria monocytogenes EGD-e. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.93Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

INLB_LISMG Mediates the entry of L.monocytogenes into normally non-phagocytic mammalian host cells (Probable) (PubMed:9282740, PubMed:11081636). Its host receptor is hepatocyte growth factor receptor (HGF receptor, a tyrosine kinase, MET) which is tyrosine-phosphorylated in response to InlB in human, green monkey, mouse and dog cell lines (PubMed:11081636, PubMed:15049825). Downstream adapter proteins GAB1 and CBL are phosphorylated in response to InlB, which also causes cell colony scattering (PubMed:11081636). InlB binding to mammalian cells is saturable and inhibited by EDTA; InlB-coated beads can be taken up by host cells (PubMed:10747014). Complement component 1 Q subcomponent-binding protein (gC1q-R, C1QBP) might act as an InlB receptor, leading to activation of PI3-kinase in green monkey cells (PubMed:10747014). Stimulation of Tyr-phosphorylation by InlB is antagonized by C1QBP, showing that potentiation of MET signaling via the GW domains is not mediated by C1QBP; the exact role of C1QBP remains to be determined (PubMed:15049825). Stimulation of Tyr-phosphorylation of MET by InlB is potentiated by the InlB GW domains and glycosaminoglycans such as heparin; exogenously added InlB, or hepatocyte growth factor (HGF) will also substitute for bacterial InlB, suggesting InlB promotes bacterial invasion by mimicking the hormone HGF (PubMed:15049825). May stimulate phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3-kinase) in green monkey cells, has less effect in humans as PI3-kinase is constitutively and highly expressed in Caco cells (Probable). Binds heparin; C1QBP and heparin seem to bind to the GW domains (PubMed:12411480).[1] [2] [3] [4] [5] [6] [7] [8]

Publication Abstract from PubMed

The physiological relevance of contacts in crystal lattices often remains elusive. This was also the case for the complex between the invasion protein internalin B (InlB) from Listeria monocytogenes and its host cell receptor, the human receptor tyrosine kinase (RTK) MET. InlB is aMET agonist and induces bacterialhost cell invasion.Activation of RTKs generally involves ligand-induced dimerization of the receptor ectodomain. The two currently available crystal structures of the InlB:MET complex show the same arrangement of InlB and MET in a 1:1 complex, but different dimeric 2:2 assemblies. Only one of these 2:2 assemblies is predicted to be stable by a computational procedure. This assembly is mainly stabilized by a contact between the Cap domain of InlB from one and the Sema domain of MET from another 1:1 complex.Here, we probe the physiological relevance of this interaction. We generatedvariants of the leucine-rich repeat (LRR) protein InlBby inserting an additional repeat between the first and the second LRR. This should allow formation of the 1:1 complex but disrupt the potential 2:2 complex involving the Cap-Sema contact due to steric distortions. A crystal structure of oneof the engineered proteins showed that it folded properly. Binding affinityto MET was comparable to that of wild-type InlB. The InlB variant induced MET phosphorylation and cell scatter like wild-type InlB.Theseresults suggestthat the Cap-Sema interaction is not physiologically relevant and support the previously proposed assembly, in which a 2:2 InlB-MET complex is built around a ligand dimer.

Engineered variants of InlB with an additional leucine-rich repeat discriminate between physiologically relevant and packing contacts in crystal structures of the InlB:MET complex.,Niemann HH, Gherardi E, Bleymuller WM, Heinz DW Protein Sci. 2012 Aug 10. doi: 10.1002/pro.2142. PMID:22887347[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Braun L, Ghebrehiwet B, Cossart P. gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogenes. EMBO J. 2000 Apr 3;19(7):1458-66. PMID:10747014 doi:10.1093/emboj/19.7.1458
  2. ↑ Shen Y, Naujokas M, Park M, Ireton K. InIB-dependent internalization of Listeria is mediated by the Met receptor tyrosine kinase. Cell. 2000 Oct 27;103(3):501-10. PMID:11081636 doi:10.1016/s0092-8674(00)00141-0
  3. ↑ Marino M, Banerjee M, Jonquieres R, Cossart P, Ghosh P. GW domains of the Listeria monocytogenes invasion protein InlB are SH3-like and mediate binding to host ligands. EMBO J. 2002 Nov 1;21(21):5623-34. PMID:12411480
  4. ↑ Banerjee M, Copp J, Vuga D, Marino M, Chapman T, van der Geer P, Ghosh P. GW domains of the Listeria monocytogenes invasion protein InlB are required for potentiation of Met activation. Mol Microbiol. 2004 Apr;52(1):257-71. PMID:15049825 doi:10.1111/j.1365-2958.2003.03968.x
  5. ↑ Braun L, Dramsi S, Dehoux P, Bierne H, Lindahl G, Cossart P. InlB: an invasion protein of Listeria monocytogenes with a novel type of surface association. Mol Microbiol. 1997 Jul;25(2):285-94. PMID:9282740 doi:10.1046/j.1365-2958.1997.4621825.x
  6. ↑ Shen Y, Naujokas M, Park M, Ireton K. InIB-dependent internalization of Listeria is mediated by the Met receptor tyrosine kinase. Cell. 2000 Oct 27;103(3):501-10. PMID:11081636 doi:10.1016/s0092-8674(00)00141-0
  7. ↑ Gaillard JL, Berche P, Frehel C, Gouin E, Cossart P. Entry of L. monocytogenes into cells is mediated by internalin, a repeat protein reminiscent of surface antigens from gram-positive cocci. Cell. 1991 Jun 28;65(7):1127-41. PMID:1905979 doi:10.1016/0092-8674(91)90009-n
  8. ↑ Ireton K, Payrastre B, Chap H, Ogawa W, Sakaue H, Kasuga M, Cossart P. A role for phosphoinositide 3-kinase in bacterial invasion. Science. 1996 Nov 1;274(5288):780-2. PMID:8864117 doi:10.1126/science.274.5288.780
  9. ↑ Niemann HH, Gherardi E, Bleymuller WM, Heinz DW. Engineered variants of InlB with an additional leucine-rich repeat discriminate between physiologically relevant and packing contacts in crystal structures of the InlB:MET complex. Protein Sci. 2012 Aug 10. doi: 10.1002/pro.2142. PMID:22887347 doi:10.1002/pro.2142

4aw4, resolution 1.93Å

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