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Structural aspects of molecular recognition in the immune system. Part II: Pattern recognition receptors


Robinson, John A; Moehle, Kerstin (2014). Structural aspects of molecular recognition in the immune system. Part II: Pattern recognition receptors. Pure and Applied Chemistry, 86(10):1483-1538.

Abstract

The vertebrate immune system uses pattern recognition receptors (PRRs) to detect a large variety of molecular signatures (pathogen-associated molecular patterns, PAMPs) from a broad range of different invading pathogens. The PAMPs range in size from relatively small molecules, to others of intermediate size such as bacterial lipopolysaccharide, lipopeptides, and oligosaccharides, to macromolecules such as viral DNA, RNA, and pathogen-derived proteins such as flagellin. Underlying this functional diversity of PRRs is a surprisingly small number of structurally distinct protein folds that include leucine-rich repeats in Toll-like receptors (TLRs) and NOD-like receptors (NLRs), the DExH box helicase domain in RIG-like receptors (RLRs), and C-type lectin domains (CTLDs) in the C-type lectins. Following PAMP recognition by the PRRs, downstream signaling pathways activate the innate immune system to respond to invading pathogenic organisms. The resulting stimulatory response is also vital for a balanced adaptive immune response to the pathogen, mediated by circulating antibodies and/or cytotoxic T cells. However, an aberrant stimulation of the innate immune system can also lead to excessive inflammatory and toxic stress responses. Exciting opportunities are now arising for the design of small synthetic molecules that bind to PRRs and influence downstream signaling pathways. Such molecules can be useful tools to modulate immune responses, for example, as adjuvants to stimulate adaptive immune responses to a vaccine, or as therapeutic agents to dampen aberrant immune responses, such as inflammation. The design of agonists or antagonists of PRRs can now benefit from a surge in knowledge of the 3D structures of PRRs, many in complexes with their natural ligands. This review article describes recent progress in structural studies of PRRs (TLRs, NLRs, CTLs, and RLRs), which is required for an understanding of how they specifically recognize structurally diverse "foreign" PAMPs amongst a background of other "self" molecules, sometimes closely related in structure, that are present in the human body.

Abstract

The vertebrate immune system uses pattern recognition receptors (PRRs) to detect a large variety of molecular signatures (pathogen-associated molecular patterns, PAMPs) from a broad range of different invading pathogens. The PAMPs range in size from relatively small molecules, to others of intermediate size such as bacterial lipopolysaccharide, lipopeptides, and oligosaccharides, to macromolecules such as viral DNA, RNA, and pathogen-derived proteins such as flagellin. Underlying this functional diversity of PRRs is a surprisingly small number of structurally distinct protein folds that include leucine-rich repeats in Toll-like receptors (TLRs) and NOD-like receptors (NLRs), the DExH box helicase domain in RIG-like receptors (RLRs), and C-type lectin domains (CTLDs) in the C-type lectins. Following PAMP recognition by the PRRs, downstream signaling pathways activate the innate immune system to respond to invading pathogenic organisms. The resulting stimulatory response is also vital for a balanced adaptive immune response to the pathogen, mediated by circulating antibodies and/or cytotoxic T cells. However, an aberrant stimulation of the innate immune system can also lead to excessive inflammatory and toxic stress responses. Exciting opportunities are now arising for the design of small synthetic molecules that bind to PRRs and influence downstream signaling pathways. Such molecules can be useful tools to modulate immune responses, for example, as adjuvants to stimulate adaptive immune responses to a vaccine, or as therapeutic agents to dampen aberrant immune responses, such as inflammation. The design of agonists or antagonists of PRRs can now benefit from a surge in knowledge of the 3D structures of PRRs, many in complexes with their natural ligands. This review article describes recent progress in structural studies of PRRs (TLRs, NLRs, CTLs, and RLRs), which is required for an understanding of how they specifically recognize structurally diverse "foreign" PAMPs amongst a background of other "self" molecules, sometimes closely related in structure, that are present in the human body.

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Additional indexing

Item Type:Journal Article, refereed, further contribution
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:October 2014
Deposited On:07 Jan 2015 10:32
Last Modified:08 Dec 2017 09:30
Publisher:DeGruyter
ISSN:0033-4545
Publisher DOI:https://doi.org/10.1515/pac-2013-1026
Official URL:http://www.degruyter.com/dg/viewarticle.fullcontentlink:pdfeventlink/$002fj$002fpac.

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