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SEF/IL-17R/CIKS/ACT1 homology (SEFIR) domain containing proteins, which include the IL-17 receptors and an adaptor protein Act1, have essential roles in vertebrate immunity. However, the molecular mechanisms of Act1 function remain largely unexplored. In this article, we employed an evolutionary analysis to discover novel structural and functional properties of Act1. Firstly, we have found that the previously identified helix-loop-helix and Ufd2-box domains in human Act1 have relatively recent evolutionary origins in higher vertebrates. Zebrafish Act1, which lacks these domains, is unable to induce JNK phosphorylation and activate cytokine expression when expressed in human cells. Secondly, we have established that Act1-like proteins contain DEATH-domains in basal animals, such as Hydra and primitive chordates, but lack this domain in vertebrates. Finally, we have shown that Act1-TRAF6 interactions are conserved throughout vertebrate evolution: Act1 derived from zebrafish can bind to TRAF6 and activate NF-κB in human cells. Moreover, we have identified a novel highly conserved motif at the amino-terminus of Act1, which is critical for binding to TRAF6 and activating NF-κB-dependent gene expression. We propose a model of evolutionary changes in Act1-mediated signalling, which contributes to a better understanding of evolution of the vertebrate immunity.

Original publication

DOI

10.1007/s00239-011-9450-7

Type

Journal article

Journal

Journal of molecular evolution

Publication Date

04/06/2011

Volume

72

Pages

521 - 530

Addresses

Kennedy Institute of Rheumatology Division, Imperial College of Science, Technology and Medicine, Hammersmith, London, UK. g.ryzhakov@imperial.ac.uk

Keywords

Animals, Vertebrates, Humans, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, TNF Receptor-Associated Factor 6, Sequence Alignment, Evolution, Molecular, Signal Transduction, Species Specificity, Gene Expression Regulation, Amino Acid Sequence, Amino Acid Motifs, Protein Binding, Models, Biological, Molecular Sequence Data, Receptors, Interleukin-17, HEK293 Cells