Death, TIR, and RHIM: Self-assembling domains involved in innate immunity and cell-death signaling

Nanson, J.D.; Kobe, Boštjan; Ve, Thomas

doi:10.1002/jlb.mr0318-123r

Cited by 48 publications

(46 citation statements)

References 123 publications

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“…The second is that the individual sites can also be "multispecific" and may interact with different TIRs with a similar affinity (Javmen et al 2018;Ve et al 2017). Recent studies have advanced our understanding of the topology of TIR domain interactions for certain TLRs and TLR adapters (Javmen et al 2018;Nanson et al 2019;Toshchakov and Javmen 2020;Ve et al 2017). This new knowledge has led to plausible models for the architecture of TLR signaling complexes (Javmen et al 2018;Ve et al 2017).…”

Section: Discussionmentioning

confidence: 99%

A survey of TIR domain sequence and structure divergence

Toshchakov

Neuwald

2020

Immunogenetics

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Toll-interleukin-1R resistance (TIR) domains are ubiquitously present in all forms of cellular life. They are most commonly found in signaling proteins, as units responsible for signal-dependent formation of protein complexes that enable amplification and spatial propagation of the signal. A less common function of TIR domains is their ability to catalyze nicotinamide adenine dinucleotide degradation. This survey analyzes 26,414 TIR domains, automatically classified based on group-specific sequence patterns presumably determining biological function, using a statistical approach termed Bayesian partitioning with pattern selection (BPPS). We examine these groups and patterns in the light of available structures and biochemical analyses. Proteins within each of thirteen eukaryotic groups (10 metazoans and 3 plants) typically appear to perform similar functions, whereas proteins within each prokaryotic group typically exhibit diverse domain architectures, suggesting divergent functions. Groups are often uniquely characterized by structural fold variations associated with group-specific sequence patterns and by herein identified sequence motifs defining TIR domain functional divergence. For example, BPPS identifies, in helices C and D of TIRAP and MyD88 orthologs, conserved surface-exposed residues apparently responsible for specificity of TIR domain interactions. In addition, BPPS clarifies the functional significance of the previously described Box 2 and Box 3 motifs, each of which is a part of a larger, group-specific block of conserved, intramolecularly interacting residues.

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Section: Discussionmentioning

confidence: 99%

A survey of TIR domain sequence and structure divergence

Toshchakov

Neuwald

2020

Immunogenetics

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“…The NLR protein super-family, which is critical in both animal and plant innate immunity, is defined by the presence of a central nucleotide binding domain (NBD) (known as NACHT in mammalian and NB-ARC in plant proteins) and a C-terminal leucine-rich repeat (LRR) domain (Meunier and Broz, 2017). Typically, animal NLRs also contain CARD (caspase-activation and recruitment) or PYD (pyrin) domains from the death-fold super-family (Nanson et al, 2019), whereas plant NLRs feature CC (coiled-coil) or TIR (Toll/interleukin-1 receptor/resistance protein) domains (Monteiro and Nishimura, 2018). In plants, CC and TIR are signaling domains, and they can induce defense responses when expressed on their own; the NBD and LRR domains perform regulatory and sensor functions.…”

Section: Introductionmentioning

confidence: 99%

The Plant “Resistosome”: Structural Insights into Immune Signaling

Burdett

Bentham

Williams

et al. 2019

Cell Host & Microbe

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Plant innate immunity is triggered via direct or indirect recognition of pathogen effectors by the NLR family immune receptors. Mechanistic understanding of plant NLR function has relied on structural information from individual NLR domains and inferences from studies on animal NLRs. Recent reports of the cryo-EM structures of the Arabidopsis plant immune receptor ZAR1 in monomeric inactive and transition states, as well as the active oligomeric state or the ''resistosome,'' have afforded a quantum leap in our understanding of how plant NLRs function. In this Review, we outline the recent structural findings and examine their implications for the activation of plant immune receptors more broadly. We also discuss how NLR signaling in plants, as illustrated by the ZAR1 structure, is analogous to innate immune receptor signaling mechanisms across kingdoms, drawing particular attention to the concept of signaling by cooperative assembly formation.

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“…Detailed structure function analysis has defined the roles of each domain for the activity of SARM1 [27]. Among these domains, only TIR domains have been previously implicated in signaling, present in Toll-like receptors and adaptors where they serve as scaffolds to recruit proteins that activate innate immune signaling [42]. As with innate immune receptors, the SARM1 TIR domain is the pro-degenerative signaling region of the SARM1 molecule.…”

Section: Sarm1 Is An Injury-activated Nad + Consuming Enzymementioning

confidence: 99%

Axon degeneration: mechanistic insights lead to therapeutic opportunities for the prevention and treatment of peripheral neuropathy

DiAntonio¹

2019

Pain

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Peripheral neuropathy is the most common neurodegenerative disease affecting hundreds of millions of patients worldwide and is an important cause of chronic pain. Typical peripheral neuropathies are characterized by dysesthesias including numbness, crawling skin, a sensation of “pins and needles,” and burning and stabbing pain. In addition, peripheral neuropathy can affect the motor and autonomic systems leading to symptoms such as weakness, constipation, and dysregulation of blood pressure. Peripheral neuropathies can be either hereditary or acquired and are a common consequence of diabetes and treatment with chemotherapy agents. Many neuropathies are due to degeneration of long axons; however, the mechanisms driving axon loss were unknown, and so no therapies are available to preserve vulnerable axons and prevent the development of peripheral neuropathy. With the recent identification of SARM1 as an injury-activated NADase enzyme that triggers axon degeneration, there is now a coherent picture emerging for the mechanism of axonal self-destruction. Here, we will present evidence that inhibiting the SARM1 pathway can prevent the development of peripheral neuropathy, describe the emerging mechanistic understanding of the axon degeneration program, and discuss how these mechanistic insights may be translated to the clinic for the prevention and treatment of peripheral neuropathy and other neurodegenerative disorders.

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Death, TIR, and RHIM: Self-assembling domains involved in innate immunity and cell-death signaling

Cited by 48 publications

References 123 publications

A survey of TIR domain sequence and structure divergence

A survey of TIR domain sequence and structure divergence

The Plant “Resistosome”: Structural Insights into Immune Signaling

Axon degeneration: mechanistic insights lead to therapeutic opportunities for the prevention and treatment of peripheral neuropathy

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