This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Toll receptors were first characterized in Drosophila melanogaster (a fruit fly) and are important for embryonic development and innate immune response. Similar receptors called Toll-like receptors (TLRs) were recently found in vertebrate genomes and play a major role in innate immunity. TLRs recognize and respond to a wide variety of pathogen-derived substances. Toll proteins and TLRs belong to a family of type I transmembrane glycoproteins with several blocks of Leucine rich repeat (LRR) regions with cysteine-rich capping elements at N- and C-terminus.Toll receptors (and TLRs) get activated when its ectodomain binds to a receptor ligand. Cytokine Sp tzle (106 amino acid motif with a molecular mass of 24 kDa in its dimeric form) is one such ligand which activates toll receptors. Sp tzle forms dimers through disulphide bonds and known to bind to Toll protein at the N-terminus. The interaction of Toll protein with Sp tzle leads to the crosslinking of ectodomains of two Toll proteins, which then leads to the signal transduction by Toll. The signaling mechanism of Toll proteins can be best understood by studying the ligand induced dimerization of the toll proteins. Despite the growing interest in structural properties of Toll receptors (molecular mass 110 kDa), their interaction with sp tzle and dimerization process, there is a lack of structural information in the available literature. Recently, the structure of Toll-like receptor (TLR3) has been solved by X-ray crystallography to an atomic resolution. Our lab is interested in studying single-particle structures reconstituted from electron microscopy images and have solved the structure of TLR3 ectodomain expressed in human cells. Recently, we have solved the structure of Toll protein and Toll-sp tzle complex using negatively stained EM micrographs and EMAN software to a resolution of about 25 . Superposition of Toll and Toll-Sp tzle structures clearly identifies the Sp tzle in the Toll-Sp tzle complex and hence the N-terminus of the protein. Also, we have a Toll-Sp tzle complex that formed dimers of toll proteins. The structure has been solved to a resolution of ~ 30 using negatively stained electron micrographs. The structure shows that the two toll proteins with sp tzle bound at their N-terminus interact with each other through their C-terminus. Interestingly, another interaction near the N-terminus of the proteins (near Sp tzle binding site) was also observed. High resolution structure of this dimer complex will help us to get the details of the interaction at the N-terminus. With this preliminary study, we are proposing to perform the cryoEM analysis of the toll protein in its dimeric form for a high resolution structure reconstruction.
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