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• W2088432422 abstract "The structure of the Deltex tandem WWE repeats reported by Barrick and colleagues in this issue of Structure reveals an intimate interface between the repeats, which together combine to create a binding site for the ankyrin repeat domain of Notch. The structure of the Deltex tandem WWE repeats reported by Barrick and colleagues in this issue of Structure reveals an intimate interface between the repeats, which together combine to create a binding site for the ankyrin repeat domain of Notch. Notch proteins are modular, single-pass transmembrane receptors that communicate essential developmental signals between adjacent cells of metazoan organisms. Depending on dose and context, the activation of Notch can drive the choice of one cell fate over another, promote cell proliferation and stem cell self-renewal, or initiate programmed cell death (Artavanis-Tsakonas et al., 1999Artavanis-Tsakonas S. Rand M.D. Lake R.J. Science. 1999; 284: 770-776Crossref PubMed Scopus (4667) Google Scholar). Pioneering studies in model organisms led to the elucidation of the canonical Notch signaling pathway, which relies on regulated intramembrane proteolysis to transduce signals. Signaling is typically initiated when protein ligands of the delta, serrate and lag-2 family expressed on the surface of one cell bind to Notch receptors on an adjacent cell. Through a poorly understood mechanism requiring endocytosis of the ligands into the ligand-expressing cell (Parks et al., 2000Parks A.L. Klueg K.M. Stout J.R. Muskavitch M.A. Development. 2000; 127: 1373-1385Crossref PubMed Google Scholar), ligand binding renders Notch sensitive to a series of proteolytic cleavages that ultimately release the intracellular portion of Notch (ICN) from the membrane, allowing it to translocate to the nucleus. In the nucleus, ICN binds to a DNA-bound transcription factor CSL (CBF-1/RBP-Jκ in mammals, Suppressor of hairless in Drosophila and Lag-1 in C. elegans); this ICN/CSL complex then recruits a coactivator of the Mastermind family to turn on transcription of target genes. Because of the exquisite sensitivity of cells to Notch signals, it is hardly surprising that the ligand-responsiveness, strength, and duration of Notch signals are modulated by a number of other gene products. Drosophila DELTEX was originally implicated in Notch signaling when it was identified in a genetic screen for loci that suppress lethality associated with certain heteroallelic combinations of the Notch Abruptex alleles, a group of dominant mutations that appear to result in enhanced Notch signaling (Xu and Artavanis-Tsakonas, 1990Xu T. Artavanis-Tsakonas S. Genetics. 1990; 126: 665-677Crossref PubMed Google Scholar). The acquisition of Deltex as a Notch modulator appears to have occurred late in evolution, because there is no apparent homolog of Deltex in C. elegans. Deltex encodes a protein with three domains: an N-terminal domain with two WWE sequence motifs, a central proline-rich region, and a C-terminal RING-E3 ubiquitin ligase domain. Early cell-based studies in fly S2 cells pointed to a direct interaction between Deltex and Notch: the two proteins colocalize in the cytoplasm near the membrane when simultaneously expressed in S2 cells, and yeast two-hybrid experiments mapped the putative interaction to the N-terminal WWE sequence repeats of Deltex and the ankyrin repeat domain of Notch (Diederich et al., 1994Diederich R.J. Matsuno K. Hing H. Artavanis-Tsakonas S. Development. 1994; 120: 473-481PubMed Google Scholar, Matsuno et al., 1995Matsuno K. Diederich R.J. Go M.J. Blaumueller C.M. Artavanis-Tsakonas S. Development. 1995; 121: 2633-2644Crossref PubMed Google Scholar). Moreover, the Abruptex suppression phenotype due to loss-of-function mutations at the DELTEX locus is mimicked by an intragenic valine for alanine mutation in the fifth ankyrin repeat of Notch (A2060V), further supporting the inference that the Notch/Deltex interaction is direct (Diederich et al., 1994Diederich R.J. Matsuno K. Hing H. Artavanis-Tsakonas S. Development. 1994; 120: 473-481PubMed Google Scholar). In this issue of Structure, Barrick and colleagues report the X-ray crystal structure of the N-terminal tandem WWE repeat domain of Drosophila Deltex, and demonstrate direct binding of this domain to the ankyrin repeat domain of Drosophila Notch using purified recombinant proteins (Zweifel et al., 2005Zweifel M.E. Leahy D.J. Barrick D. Structure. 2005; 13 (this issue): 1599-1611Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). Though the precise topology of the WWE fold is novel, each WWE module superficially resembles ubiquitin. Two clusters of conserved tryptophan, arginine, and glutamate residues participate in defining the fold of each WWE module and contribute to the stability of the WWE domain composed of the module pair (Zweifel et al., 2005Zweifel M.E. Leahy D.J. Barrick D. Structure. 2005; 13 (this issue): 1599-1611Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). The structure, together with biophysical studies of domain unfolding, clarifies why the WWE repeats occur as a pair: the two repeats share an extensive interdomain interface that is stabilized in part by an extended short polypeptide segment immediately following the end of the second repeat that packs against the N-terminal β strand of the first repeat (Zweifel et al., 2005Zweifel M.E. Leahy D.J. Barrick D. Structure. 2005; 13 (this issue): 1599-1611Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). Combined with biochemical studies, the WWE domain structure also suggests that charged residues on the surfaces of the interacting partners are likely to constitute key features of the binding interface. Because the surface of Notch is predominantly acidic (Figure 1A), especially near the alanine at position 2060 of the fifth ankyrin repeat, one particular patch of basic residues adjacent to a narrow cleft between the WWE repeats (Figure 1B) merits consideration as a putative contact site; this possibility can now be easily tested by site-directed mutagenesis. Because loss of Deltex function suppresses Notch hyperactivity, and because loss-of-function phenotypes are synthetic lethal with certain hypomorphic Notch alleles, the early genetic evidence in flies led to the conclusion that Deltex is a positive regulator of Notch activity (Matsuno et al., 1995Matsuno K. Diederich R.J. Go M.J. Blaumueller C.M. Artavanis-Tsakonas S. Development. 1995; 121: 2633-2644Crossref PubMed Google Scholar, Xu and Artavanis-Tsakonas, 1990Xu T. Artavanis-Tsakonas S. Genetics. 1990; 126: 665-677Crossref PubMed Google Scholar). On the other hand, more recent studies in mammals have shown that Deltex1 (one of four mammalian Deltex homologs) acts as an antagonist of Notch signaling in models of neurite outgrowth, lymphoid development, and mammary carcinogenesis (Izon et al., 2002Izon D.J. Aster J.C. He Y. Weng A. Karnell F.G. Patriub V. Xu L. Bakkour S. Rodriguez C. Allman D. Pear W.S. Immunity. 2002; 16: 231-243Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, Kiaris et al., 2004Kiaris H. Politi K. Grimm L.M. Szabolcs M. Fisher P. Efstratiadis A. Artavanis-Tsakonas S. Am. J. Pathol. 2004; 165: 695-705Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, Sestan et al., 1999Sestan N. Artavanis-Tsakonas S. Rakic P. Science. 1999; 286: 741-746Crossref PubMed Scopus (480) Google Scholar). Yet another possibility is that Deltex participates in a CSL-independent branch of Notch signaling, though the effectors responsible for CSL-independent Notch signaling and the events that trigger it remain poorly defined. The most recent genetic and functional data implicate Deltex in Notch endocytosis and trafficking, a possibility first suggested by genetic studies that place Deltex activity downstream of full-length Notch but upstream of ICN. Enforced expression of Deltex in Drosophila leads to depletion of Notch from the cell surface and accumulation of Notch intracellularly in endocytic vesicles (Hori et al., 2004Hori K. Fostier M. Ito M. Fuwa T.J. Go M.J. Okano H. Baron M. Matsuno K. Development. 2004; 131: 5527-5537Crossref PubMed Scopus (149) Google Scholar). Moreover, Deltex functionally antagonizes Suppressor of Deltex and its homolog NEDD4, proteins proposed to inactivate Notch molecules by directing them to an intracellular compartment for degradation (Sakata et al., 2004Sakata T. Sakaguchi H. Tsuda L. Higashitani A. Aigaki T. Matsuno K. Hayashi S. Curr. Biol. 2004; 14: 2228-2236Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, Wilkin et al., 2004Wilkin M.B. Carbery A.M. Fostier M. Aslam H. Mazaleyrat S.L. Higgs J. Myat A. Evans D.A. Cornell M. Baron M. Curr. Biol. 2004; 14: 2237-2244Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). How might Deltex promote Notch endocytosis? Proteomic studies by Artavanis-Tsakonas's group have identified a complex between the β-arrestin homolog Kurtz and Deltex (Veraksa et al., 2005Veraksa A. Bauer A. Artavanis-Tsakonas S. Dev. Dyn. 2005; 232: 827-834Crossref PubMed Scopus (84) Google Scholar). Non-visual β-arrestins are versatile adaptor proteins that regulate the signaling and trafficking of different classes of receptors (Shenoy and Lefkowitz, 2003Shenoy S.K. Lefkowitz R.J. Biochem. J. 2003; 375: 503-515Crossref PubMed Scopus (325) Google Scholar) and it may be that Kurtz connects Notch/Deltex complexes to the endocytic machinery or otherwise influences their fate, perhaps even by inactivating them in a way that may depend on the E3 ubiquitin ligase activity associated with mammalian Deltex proteins (Takeyama et al., 2003Takeyama K. Aguiar R.C. Gu L. He C. Freeman G.J. Kutok J.L. Aster J.C. Shipp M.A. J. Biol. Chem. 2003; 278: 21930-21937Crossref PubMed Scopus (85) Google Scholar). It is also attractive to speculate that Deltex/Kurtz complexes act as a CSL-independent sensor for Notch activation, thereby serving to integrate the effects of Notch activation with other signaling events influenced by β-arrestins, like those transduced by G proteins, Wnt proteins, or TGF-β family molecules. Having the structure of the WWE domain of Deltex in hand represents an important first step toward sorting among these various possibilities for the role of Deltex as a modulator of Notch signaling." @default.
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• W2088432422 date "2005-11-01" @default.
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• W2088432422 title "A New Niche for Notch on Deltex?" @default.
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