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Evolutionary emergence of Hairless as a novel component of the Notch signaling pathway.

ABSTRACT: Suppressor of Hairless [Su(H)], the transcription factor at the end of the Notch pathway in Drosophila, utilizes the Hairless protein to recruit two co-repressors, Groucho (Gro) and C-terminal Binding Protein (CtBP), indirectly. Hairless is present only in the Pancrustacea, raising the question of how Su(H) in other protostomes gains repressive function. We show that Su(H) from a wide array of arthropods, molluscs, and annelids includes motifs that directly bind Gro and CtBP; thus, direct co-repressor recruitment is ancestral in the protostomes. How did Hairless come to replace this ancestral paradigm? Our discovery of a protein (S-CAP) in Myriapods and Chelicerates that contains a motif similar to the Su(H)-binding domain in Hairless has revealed a likely evolutionary connection between Hairless and Metastasis-associated (MTA) protein, a component of the NuRD complex. Sequence comparison and widely conserved microsynteny suggest that S-CAP and Hairless arose from a tandem duplication of an ancestral MTA gene.

SUBMITTER: Miller SW

PROVIDER: S-EPMC6777938 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Evolutionary emergence of Hairless as a novel component of the Notch signaling pathway.

Miller Steven W SW Movsesyan Artem A Zhang Sui S Fernández Rosa R Posakony James W JW

eLife 20190923

Suppressor of Hairless [Su(H)], the transcription factor at the end of the Notch pathway in <i>Drosophila</i>, utilizes the Hairless protein to recruit two co-repressors, Groucho (Gro) and C-terminal Binding Protein (CtBP), indirectly. Hairless is present only in the Pancrustacea, raising the question of how Su(H) in other protostomes gains repressive function. We show that Su(H) from a wide array of arthropods, molluscs, and annelids includes motifs that directly bind Gro and CtBP; thus, direct ...[more]

PMID: 31545167

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Project description:BackgroundThe Notch signaling pathway is fundamental to the regulation of many cell fate decisions in eumetazoans. Not surprisingly, members of this pathway are highly conserved even between vertebrates and invertebrates. There is one notable exception, Hairless, which acts as a general Notch antagonist in Drosophila. Hairless silences Notch target genes by assembling a repressor complex together with Suppressor of Hairless [Su(H)] and the co-repressors Groucho (Gro) and C-terminal binding protein (CtBP). Now with the availability of genomic databases, presumptive Hairless homologues are predicted, however only in insect species. To further our understanding of Hairless structure and function, we have cloned the Hairless gene from Apis mellifera (A.m.H) and characterized its functional conservation in Drosophila.ResultsThe Apis Hairless protein is only one third of the size of the Drosophila orthologue. Interestingly, the defined Suppressor of Hairless binding domain is interrupted by a nonconserved spacer sequence and the N-terminal motif is sufficient for binding. In contrast to Apis Hairless, the Drosophila orthologue contains a large acidic domain and we provide experimental evidence that this acidic domain is necessary to silence Hairless activity in vivo. Despite the dramatic size differences, Apis Hairless binds to the Drosophila Hairless interactors Su(H), Gro, CtBP and Pros26.4. Hence, Apis Hairless assembles a repressor complex with Drosophila components that may have a different topology. Nevertheless, Apis Hairless is sufficient to repress the Notch target gene vestigial in Drosophila. Moreover, it is able to rescue Hairless mutant phenotypes, providing in vivo evidence for its function as a bona fide Notch antagonist.ConclusionThis is the first interspecies-complementation analysis of the Hairless gene. Guided by evolutionary comparisons, we hope to eventually identify all the relevant structural domains and cofactors of Hairless, thereby opening an avenue for further insights into the repressor-complexes that down-regulate Notch signaling also in other, higher eukaryotes.

Project description:IntroductionToll-like receptors 4 (TLR4) recognize lipopolysaccharides (LPS) from bacteria as their conventional ligands and undergo downstream signaling to produce cytokines. They mediate the signaling either by the TIRAP-MyD88 complex or by the TRAM-TRIF complex. The MyD88 pathway is common to all other TLRs, whereas the TRAM-TRIF complex is largely exclusive to TLR4. Here we study the TIR domain of TRAM and TRIF ortholog proteins that are crucial for downstream signaling. Our previous work on pan-genome-wide survey, indicates Callorhincus milli to be the ancestral organism with both TRAM and TRIF proteins.MethodsTo gain a deeper insight into the protein function and to compare them with Homo sapiens adaptor proteins, we modeled the docking of the TRAM-TRIF complex of representative organisms across various taxa. These modeling experiments provide insights to ascertain a possible interaction surface and calculate the energetics and electrostatic potential of the complex. Furthermore, this enables us to employ normal mode analysis (NMA) to examine fluctuating, interacting, and other specific residue clusters that could have a role in protein functioning in both C. milli and H. sapiens. We also performed molecular dynamics simulations of these complexes and cross-validated the functionally important residues using network parameters.ResultsWe compared the stoichiometry of TRAM-TRIF complexes and found that the tetrameric models (TRAM and TRIF dimer) were more stable than the trimeric model (TRAM dimer and TRIF monomer). While the critical residues of TIRAP, TRIF, and MyD88 were preserved, we also found that the important residues of TRAM signaling were not conserved in C. milli.DiscussionThis suggests the presence of functional TIRAP-MyD88-mediated TLR4 signaling and TRIF-mediated TLR3 signaling in the ancestral species. The overall biological function of this signaling domain appears to be gradually acquired through the orchestration of several motifs through an evolutionary scale.

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Evolutionary emergence of Hairless as a novel component of the Notch signaling pathway.

Publications

Evolutionary emergence of Hairless as a novel component of the Notch signaling pathway.

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