Inhibition of Toll-like receptors TLR4 and 7 signaling pathways by SIGIRR: A computational approach

被引:59
作者
Gong, Jing [1 ,2 ]
Wei, Tiandi [1 ,2 ]
Stark, Robert W. [1 ,2 ]
Jamitzky, Ferdinand [1 ,3 ]
Heckl, Wolfgang M. [1 ,4 ,5 ]
Anders, Hans J. [6 ]
Lech, Maciej [6 ]
Roessle, Shaila C. [2 ]
机构
[1] Univ Munich, Ctr Nanosci, D-80799 Munich, Germany
[2] Univ Munich, Dept Earth & Environm Sci, D-80333 Munich, Germany
[3] Leibniz Supercomp Ctr, D-85748 Garching, Germany
[4] Tech Univ Munich, TUM Sch Educ, D-80799 Munich, Germany
[5] Deutsch Museum, D-80538 Munich, Germany
[6] Univ Munich, Med Poliklin, D-80336 Munich, Germany
关键词
SIGIRR; TIR8; Toll-like receptor; Homology modeling; Protein interaction; Autoimmune disease; STRUCTURAL BASIS; TIR-DOMAIN; PROTEIN STRUCTURES; QUALITY ASSESSMENT; CRYSTAL-STRUCTURE; ADAPTER PROTEINS; MYD88; RECOGNITION; RECRUITMENT; MODELS;
D O I
10.1016/j.jsb.2009.12.007
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Toll-like receptors (TLRs) belong to the Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) superfamily which is defined by a common cytoplasmic Toll/interleukin-1 receptor (TIR) domain. TLRs recognize pathogen-associated molecular patterns and initiate an intracellular kinase cascade to trigger an immediate defensive response. SIGIRR (single immunoglobulin interleukin-1 receptor-related molecule), another member of the TLR/IL-1R superfamily, acts as a negative regulator of MyD88-dependent TLR signaling. It attenuates the recruitment of MyD88 adaptors to the receptors with its intracellular TIR domain. Thus, SIGIRR is a highly important molecule for the therapy of autoimmune diseases caused by TLRs. So far, the structural mechanism of interactions between SIGIRR, TLRs and adaptor molecules is unclear. To develop a working hypothesis for this interaction, we constructed three-dimensional models for the TIR domains of TLR4, TLR7, MyD88 and SIGIRR based on computational modeling. Through protein-protein docking analysis, we developed models of essential complexes involved in the TLR4 and 7 signaling and the SIGIRR inhibiting processes. We suggest that SIGIRR may exert its inhibitory effect through blocking the molecular interface of TLR4, TLR7 and the MyD88 adaptor mainly via its BB-loop region. (C) 2009 Elsevier Inc. All rights reserved.
引用
收藏
页码:323 / 330
页数:8
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