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Mice, men and the relatives: cross-species studies underpin innate immunity.

Bryant CE, Monie TP - Open Biol (2012)

Bottom Line: Information obtained from Drospohila melanogaster, knock-out and knock-in mice, and through the use of forward genetics has resulted in discoveries that have opened our eyes to the functionality and complexity of the innate immune system.With the current increase in genomic information, the range of innate immune receptors and pathways of other species available to study is rapidly increasing, and provides a rich resource to continue the development of innate immune research.Here, we address some of the highlights of cross-species study in the innate immune field and consider the benefits of widening the species-field further.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.

ABSTRACT
The innate immune response is the first line of defence against infection. Germ-line-encoded receptors recognize conserved molecular motifs from both exogenous and endogenous sources. Receptor activation results in the initiation of a pro-inflammatory immune response that enables the resolution of infection. Understanding the inner workings of the innate immune system is a fundamental requirement in the search to understand the basis of health and disease. The development of new vaccinations, the treatment of pathogenic infection, the generation of therapies for chronic and auto-inflammatory disorders, and the ongoing battle against cancer, diabetes and atherosclerosis will all benefit from a greater understanding of innate immunity. The rate of knowledge acquisition in this area has been outstanding. It has been underpinned and driven by the use of model organisms. Information obtained from Drospohila melanogaster, knock-out and knock-in mice, and through the use of forward genetics has resulted in discoveries that have opened our eyes to the functionality and complexity of the innate immune system. With the current increase in genomic information, the range of innate immune receptors and pathways of other species available to study is rapidly increasing, and provides a rich resource to continue the development of innate immune research. Here, we address some of the highlights of cross-species study in the innate immune field and consider the benefits of widening the species-field further.

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Related in: MedlinePlus

Timeline of TLR ectodomain structural characterization. The list to date of current structures of TLR ectodomains from humans, mice and zebrafish are shown in conjunction with their Protein Data Bank (PDB) identifies. Murine and zebrafish structures are presented in ribbon format and images were generated using the PyMOL molecular graphics system, v. 1.3, Schrödinger, LLC. Years highlighted in bright blue (2006, 2010, 2011) correspond to those in which no TLR ectodomain structures were published. PDB files are associated with the following references: PDB 1ziw [35]; PDB 2a0z [36]; PDBs 2z62, 2z63, 2z64, 2z65, 2z66 [37]; PDBs 2z80, 2z81, 2z82, 2z7x [38]; PDB 3ciy [39]; PDB 3fxi [40]; PDBs 3a79, 3a7b, 3a7c [41]; and PDBs 3v44, 3v47 [42]. VLR, variable lymphocyte receptor.
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RSOB120015F1: Timeline of TLR ectodomain structural characterization. The list to date of current structures of TLR ectodomains from humans, mice and zebrafish are shown in conjunction with their Protein Data Bank (PDB) identifies. Murine and zebrafish structures are presented in ribbon format and images were generated using the PyMOL molecular graphics system, v. 1.3, Schrödinger, LLC. Years highlighted in bright blue (2006, 2010, 2011) correspond to those in which no TLR ectodomain structures were published. PDB files are associated with the following references: PDB 1ziw [35]; PDB 2a0z [36]; PDBs 2z62, 2z63, 2z64, 2z65, 2z66 [37]; PDBs 2z80, 2z81, 2z82, 2z7x [38]; PDB 3ciy [39]; PDB 3fxi [40]; PDBs 3a79, 3a7b, 3a7c [41]; and PDBs 3v44, 3v47 [42]. VLR, variable lymphocyte receptor.

Mentions: Determination of the molecular structure of pattern recognition receptors has proved to be difficult. Only in the last few years have we begun to understand the molecular detail involved in ligand recognition for the TLRs with the gradual solving of the apo- and ligand-bound forms of a selection of TLR ectodomains (figure 1). This began in 2005 when the apo-form of human TLR3 was solved independently by two separate research groups [35,36]. These structures provided the first experimental confirmation that the TLR LRR ectodomain did indeed form the type of solenoid-like structure that had been predicted. Producing sufficient quantities of purified protein for structural characterization has proved to be an arduous task for these proteins. It was another 2 years before any further TLR ectodomain structures were published. These were made feasible by the development of J.-O. Lee's work using variable lymphocyte receptor (VLR) capping techniques [43]. The VLR is an LRR-containing protein involved in the adaptive immune response of the sea lamprey. Following from the successful structural characterization of the VLR itself [44], the inspired approach of adding VLR capping structures onto the N- and C-termini, either individually or in parallel, of TLR ectodomains was initiated. This was feasible owing to the similar repeat size and consensus sequence between VLRs and TLRs [43,45]. The use of VLR capping technology has to date facilitated the high-resolution crystal structures of: human TLR4 in complex with MD2 and the antagonist Eritoran [37]; human and murine TLR2 in complex with various ligands [38,41]; a human TLR2:TLR1 heterodimer [38]; a murine TLR2:TLR6 heterodimer [41]; and, most recently, zebrafish TLR5 in complex with flagellin [42]. Interestingly, the structure of the active complex of TLR4:MD-2:LPS was solved without the need for VLR capping [40]. These structures provide a fantastic example of how merging protein sequences from different species can result in a hybrid protein conducive to downstream analysis, thereby significantly enhancing our biological understanding of TLR activation.Figure 1.


Mice, men and the relatives: cross-species studies underpin innate immunity.

Bryant CE, Monie TP - Open Biol (2012)

Timeline of TLR ectodomain structural characterization. The list to date of current structures of TLR ectodomains from humans, mice and zebrafish are shown in conjunction with their Protein Data Bank (PDB) identifies. Murine and zebrafish structures are presented in ribbon format and images were generated using the PyMOL molecular graphics system, v. 1.3, Schrödinger, LLC. Years highlighted in bright blue (2006, 2010, 2011) correspond to those in which no TLR ectodomain structures were published. PDB files are associated with the following references: PDB 1ziw [35]; PDB 2a0z [36]; PDBs 2z62, 2z63, 2z64, 2z65, 2z66 [37]; PDBs 2z80, 2z81, 2z82, 2z7x [38]; PDB 3ciy [39]; PDB 3fxi [40]; PDBs 3a79, 3a7b, 3a7c [41]; and PDBs 3v44, 3v47 [42]. VLR, variable lymphocyte receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376732&req=5

RSOB120015F1: Timeline of TLR ectodomain structural characterization. The list to date of current structures of TLR ectodomains from humans, mice and zebrafish are shown in conjunction with their Protein Data Bank (PDB) identifies. Murine and zebrafish structures are presented in ribbon format and images were generated using the PyMOL molecular graphics system, v. 1.3, Schrödinger, LLC. Years highlighted in bright blue (2006, 2010, 2011) correspond to those in which no TLR ectodomain structures were published. PDB files are associated with the following references: PDB 1ziw [35]; PDB 2a0z [36]; PDBs 2z62, 2z63, 2z64, 2z65, 2z66 [37]; PDBs 2z80, 2z81, 2z82, 2z7x [38]; PDB 3ciy [39]; PDB 3fxi [40]; PDBs 3a79, 3a7b, 3a7c [41]; and PDBs 3v44, 3v47 [42]. VLR, variable lymphocyte receptor.
Mentions: Determination of the molecular structure of pattern recognition receptors has proved to be difficult. Only in the last few years have we begun to understand the molecular detail involved in ligand recognition for the TLRs with the gradual solving of the apo- and ligand-bound forms of a selection of TLR ectodomains (figure 1). This began in 2005 when the apo-form of human TLR3 was solved independently by two separate research groups [35,36]. These structures provided the first experimental confirmation that the TLR LRR ectodomain did indeed form the type of solenoid-like structure that had been predicted. Producing sufficient quantities of purified protein for structural characterization has proved to be an arduous task for these proteins. It was another 2 years before any further TLR ectodomain structures were published. These were made feasible by the development of J.-O. Lee's work using variable lymphocyte receptor (VLR) capping techniques [43]. The VLR is an LRR-containing protein involved in the adaptive immune response of the sea lamprey. Following from the successful structural characterization of the VLR itself [44], the inspired approach of adding VLR capping structures onto the N- and C-termini, either individually or in parallel, of TLR ectodomains was initiated. This was feasible owing to the similar repeat size and consensus sequence between VLRs and TLRs [43,45]. The use of VLR capping technology has to date facilitated the high-resolution crystal structures of: human TLR4 in complex with MD2 and the antagonist Eritoran [37]; human and murine TLR2 in complex with various ligands [38,41]; a human TLR2:TLR1 heterodimer [38]; a murine TLR2:TLR6 heterodimer [41]; and, most recently, zebrafish TLR5 in complex with flagellin [42]. Interestingly, the structure of the active complex of TLR4:MD-2:LPS was solved without the need for VLR capping [40]. These structures provide a fantastic example of how merging protein sequences from different species can result in a hybrid protein conducive to downstream analysis, thereby significantly enhancing our biological understanding of TLR activation.Figure 1.

Bottom Line: Information obtained from Drospohila melanogaster, knock-out and knock-in mice, and through the use of forward genetics has resulted in discoveries that have opened our eyes to the functionality and complexity of the innate immune system.With the current increase in genomic information, the range of innate immune receptors and pathways of other species available to study is rapidly increasing, and provides a rich resource to continue the development of innate immune research.Here, we address some of the highlights of cross-species study in the innate immune field and consider the benefits of widening the species-field further.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.

ABSTRACT
The innate immune response is the first line of defence against infection. Germ-line-encoded receptors recognize conserved molecular motifs from both exogenous and endogenous sources. Receptor activation results in the initiation of a pro-inflammatory immune response that enables the resolution of infection. Understanding the inner workings of the innate immune system is a fundamental requirement in the search to understand the basis of health and disease. The development of new vaccinations, the treatment of pathogenic infection, the generation of therapies for chronic and auto-inflammatory disorders, and the ongoing battle against cancer, diabetes and atherosclerosis will all benefit from a greater understanding of innate immunity. The rate of knowledge acquisition in this area has been outstanding. It has been underpinned and driven by the use of model organisms. Information obtained from Drospohila melanogaster, knock-out and knock-in mice, and through the use of forward genetics has resulted in discoveries that have opened our eyes to the functionality and complexity of the innate immune system. With the current increase in genomic information, the range of innate immune receptors and pathways of other species available to study is rapidly increasing, and provides a rich resource to continue the development of innate immune research. Here, we address some of the highlights of cross-species study in the innate immune field and consider the benefits of widening the species-field further.

Show MeSH
Related in: MedlinePlus