Structural studies of pre-mRNA 3′-end processing
Acta Crystallographica Section A(2008)
摘要
Toll-like Receptors (TLRs) are central to vertebrate innate immune responses.To facilitate soluble expression and crystallization of human TLRs with bound ligands, we have developed a novel technique that we term the Hybrid LRR Technique.The hagfish VLR proteins were chosen as the fusion partners and connected to human TLRs at the conserved LxxLxLxxN regions.The hybrid LRR technique neither interrupts function of TLR nor causes substantial structural changes.TLR4 and MD-2 form a heterodimer that recognizes LPS from Gram negative bacteria.TLR2 in association with TLR1 or TLR6 responses to microbial lipoproteins and lipopeptides.The crystal structures reveal that TLR1, 2 and 4 are atypical members of the LRR family and are composed of N-terminal, central and C-terminal domains.The beta sheet of the central domain shows unusually small radii and large twist angles.MD-2 binds to the concave surface of the N-terminal and central domains of TLR4.The interaction with Eritoran, a candidate antisepsis drug, is mediated by a hydrophobic internal pocket in MD-2.Binding of the tri-acylated lipopeptide, Pam3CSK4, induced the formation of an m shaped heterodimer of the TLR1 and TLR2 ectodomains whereas binding of the di-acylated lipopeptide, Pam2CSK4 did not.The three lipid chains of Pam3CSK4 mediate the heterodimerization of the receptor; the two ester-bound lipid chains are inserted into a pocket in TLR2, while the amide-bound lipid chain is inserted into a hydrophobic channel in TLR1.An extensive hydrogen bonding network, as well as hydrophobic interactions, between TLR1 and TLR2 further stabilize the heterodimer.We propose that formation of the TLR dimer brings the intracellular TIR domains close to each other to promote dimerization and initiate signaling.
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关键词
protein complex,ribonucleases,protein crystallization and in situ proteolysis
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