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A communication network within the cytoplasmic domain of toll-like receptors has remained conserved during evolution.

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title A communication network within the cytoplasmic domain of toll-like receptors has remained conserved during evolution.
 
Creator Singh, Shikha
Pandey, Kalpana
Rathore, Yogendra S
Sagar, Amin
Pattnaik, U Bharat K
Ganguly, Ashish
 
Subject QD Chemistry
 
Description Toll/IL-1R (TIR) domain, that is, the cytoplasmic domain, in toll-like receptors (TLRs) from different species showed high sequence conservation in stretches spread across the surface as well as the core of the domain. To probe the structure-function significance of these residues, especially those coming from the core of TIR domains, we analyzed molecular dynamics trajectories of sequence similarity based models of human TIR domains. This study brought forth that N-terminal of the TIR domain simultaneously interacts with the flanking residues of the BB loop and central β-sheets. At the same time, residues of the central β-strands form favorable contacts with the DD loop and C-terminal, thus forming a two-way circuit between the N- and C-termini. In this work, the array of intradomain interactions is termed as communication network. Importantly, the "hubs" of this communication network were found to be conserved in all human TLRs. Earlier mutagenesis-function correlation work brought forth that certain mutations in the "core" of the TIR domain of TLR4 (e.g. in IFI767-769AAA and L815A) led to almost complete abrogation of signaling and reasoning for this dramatic loss-of-function has remained unclear, since these sites are not surface exposed. Using MD studies, we show here that this communication network gets disrupted in mutants of human TLR4 which were earlier reported to be functionally compromised. Extension of MD studies to heterodimer of TLR1/2 suggested that this evolutionarily conserved communication network senses the interactions formed upon dimerization and relays it to surfaces which are not involved in direct interdomain contacts.
 
Publisher Taylor & Francis
 
Date 2013-04-19
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://crdd.osdd.net/open/1292/1/ashish13.pdf
Singh, Shikha and Pandey, Kalpana and Rathore, Yogendra S and Sagar, Amin and Pattnaik, U Bharat K and Ganguly, Ashish (2013) A communication network within the cytoplasmic domain of toll-like receptors has remained conserved during evolution. Journal of biomolecular structure & dynamics. ISSN 1538-0254
 
Relation http://www.tandfonline.com/doi/full/10.1080/07391102.2013.787545#.Ucgs0dhCmNY
http://crdd.osdd.net/open/1292/