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, Volume 62, Issue 5, pp 263–272

First Online: 02 March 2010Received: 18 September 2009Accepted: 03 February 2010


In animals, the innate immune system is the first line of defense against invading microorganisms, and the pattern-recognition receptors PRRs are the key components of this system, detecting microbial invasion and initiating innate immune defenses. Two families of PRRs, the intracellular NOD-like receptors NLRs and the transmembrane Toll-like receptors TLRs, are of particular interest because of their roles in a number of diseases. Understanding the evolutionary history of these families and their pattern of evolutionary changes may lead to new insights into the functioning of this critical system. We found that the evolution of both NLR and TLR families included massive species-specific expansions and domain shuffling in various lineages, which resulted in the same domain architectures evolving independently within different lineages in a process that fits the definition of parallel evolution. This observation illustrates both the dynamics of the innate immune system and the effects of -combinatorially constrained- evolution, where existence of the limited numbers of functionally relevant domains constrains the choices of domain architectures for new members in the family, resulting in the emergence of independently evolved proteins with identical domain architectures, often mistaken for orthologs.

KeywordsParallel evolution Lineage-specific expansion Domain shuffling NOD-like receptor Toll-like receptor Innate immunity AbbreviationsBIRbaculovirus inhibitor of apoptosis repeat

CARDcaspase recruitment domain

CIITAMHC class II transactivator

DAMPsdamage-associated molecular patterns


IL-1Rinterleukin-1 receptor

IPAFICE IL-1β converting enzyme protease activating factor

LRRsleucine-rich repeats

MyD88myeloid differentiation factor 88

NACHTdomain present in NAIP, CIITA, HET-E, and TP1

NAIPneuronal apoptosis inhibitory protein

NALPsNACHT, LRR, and PYRIN domain-containing proteins

NLRsNOD-like receptors

PAMPspathogen-associated molecular patterns

PRRspattern-recognition receptors

PYRIN also known as PAAD, PYD, or DAPIN domainthe N-terminal domain of protein pyrin

SARMsterile α and HEAT-Armadillo motifs containing protein

TIRToll-interleukin-1 receptor

TIRAPTIR domain containing adaptor protein

TLRsToll-like receptors

TRAMTRIF-related adaptor molecule

TRIFTIR domain-containing adaptor inducing interferon-β

Qing Zhang and Christian M. Zmasek contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1007-s00251-010-0428-1 contains supplementary material, which is available to authorized users.

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Autor: Qing Zhang - Christian M. Zmasek - Adam Godzik


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