Delimitation of the Pore in Tweety Homolog 1 Channels: A Model-guided Approach

Reyes, José Santos; Castillo-Hernández, Jesús; Maldonado‐Cervantes, Martha Imelda; Maldonado-Cervantes, E; López, A; Hernández, A.; García-Rangel, M

doi:10.9734/jabb/2016/29145

Cited by 2 publications

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“…Since the only currently known mechanistic function of Ttyh1 is a maxi‐Cl − ion channel , we tested if the Cl − ion channel activity contributed to Notch signaling pathway. Reyes et al showed that the R371 residue of Ttyh1 provides the electrostatic basis for the selectivity filter preferring anions over cations, and the R371Q mutation resulted in a pore more permeable to cations. We found that a Ttyh1 R371Q mutant increased Notch target gene expression in vitro and induced cell localization in the VZ/SVZ in vivo comparable to wild type, suggesting that the Notch‐enhancing activity of Ttyh1 is not linked to Cl − channel activity (Fig A and C).…”

Section: Resultsmentioning

confidence: 99%

Ttyh1 regulates embryonic neural stem cell properties by enhancing the Notch signaling pathway

et al. 2018

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Despite growing evidence linking tweety-homologue 1 (Ttyh1) to normal mammalian brain development and cell proliferation, its exact role has not yet been determined. Here, we show that Ttyh1 is required for the maintenance of neural stem cell (NSC) properties as assessed by neurosphere formation and analyses of cell localization after electroporation. We find that enhanced Ttyh1-dependent stemness of NSCs is caused by enhanced γ-secretase activity resulting in increased levels of Notch intracellular domain (NICD) production and activation of Notch targets. This is a unique function of Ttyh1 among all other Ttyh family members. Molecular analyses revealed that Ttyh1 binds to the regulator of γ-secretase activity Rer1 in the endoplasmic reticulum and thereby destabilizes Rer1 protein levels. This is the key step for Ttyh1-dependent enhancement of γ-secretase activity, as Rer1 overexpression completely abolishes the effects of Ttyh1 on NSC maintenance. Taken together, these findings indicate that Ttyh1 plays an important role during mammalian brain development by positively regulating the Notch signaling pathway through the downregulation of Rer1.

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Section: Resultsmentioning

confidence: 99%

Ttyh1 regulates embryonic neural stem cell properties by enhancing the Notch signaling pathway

et al. 2018

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Structures of tweety homolog proteins TTYH2 and TTYH3 reveal a Ca2+-dependent switch from intra- to intermembrane dimerization

Hoel

Brohawn

2021

Nat Commun

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Tweety homologs (TTYHs) comprise a conserved family of transmembrane proteins found in eukaryotes with three members (TTYH1-3) in vertebrates. They are widely expressed in mammals including at high levels in the nervous system and have been implicated in cancers and other diseases including epilepsy, chronic pain, and viral infections. TTYHs have been reported to form Ca2+- and cell volume-regulated anion channels structurally distinct from any characterized protein family with potential roles in cell adhesion, migration, and developmental signaling. To provide insight into TTYH family structure and function, we determined cryo-EM structures of Mus musculus TTYH2 and TTYH3 in lipid nanodiscs. TTYH2 and TTYH3 adopt a previously unobserved fold which includes an extended extracellular domain with a partially solvent exposed pocket that may be an interaction site for hydrophobic molecules. In the presence of Ca2+, TTYH2 and TTYH3 form homomeric cis-dimers bridged by extracellularly coordinated Ca2+. Strikingly, in the absence of Ca2+, TTYH2 forms trans-dimers that span opposing membranes across a ~130 Å intermembrane space as well as a monomeric state. All TTYH structures lack ion conducting pathways and we do not observe TTYH2-dependent channel activity in cells. We conclude TTYHs are not pore forming subunits of anion channels and their function may involve Ca2+-dependent changes in quaternary structure, interactions with hydrophobic molecules near the extracellular membrane surface, and/or association with additional protein partners.

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Delimitation of the Pore in Tweety Homolog 1 Channels: A Model-guided Approach

Cited by 2 publications

References 0 publications

Ttyh1 regulates embryonic neural stem cell properties by enhancing the Notch signaling pathway

Ttyh1 regulates embryonic neural stem cell properties by enhancing the Notch signaling pathway

Structures of tweety homolog proteins TTYH2 and TTYH3 reveal a Ca2+-dependent switch from intra- to intermembrane dimerization

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