Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations.
Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations.
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DOI：
10.1038/s41467-023-40213-0
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发表时间：
2023-07-29
影响因子：
16.6
通讯作者：
Schulte, Gunnar
中科院分区：
文献类型：
--
作者：
Gratz, Lukas;Kowalski-Jahn, Maria;Scharf, Magdalena M.;Kozielewicz, Pawel;Jahn, Michael;Bous, Julien;Lambert, Nevin A.;Gloriam, David E.;Schulte, Gunnar
G蛋白偶联受体（GPCR）的卷曲类，包括10个卷曲（FZD 1 -10）旁系同源物和平滑，仍然是最神秘的GPCR家族之一。这类主要通过Disheveled（DVL）或异源三聚体G蛋白介导信号传导。然而，途径选择的机制是难以捉摸的。在这里，我们采用了结构驱动的诱变方法，结合广泛的面板功能信号读出，以调查的重要性，保守的状态稳定残基FZD 5信号规范。FZD 4和FZD 10获得了类似的数据，表明我们的发现可以外推到FZD家族的其他成员。野生型和选择的FZD 5突变体的比较分子动力学模拟进一步支持FZD中的不同构象变化指定信号结果的概念。总之，我们发现，FZD 5和FZD在一般情况下更喜欢耦合到DVL，而不是异源三聚体G蛋白和不同的活性状态的微开关的受体是必不可少的途径选择争论的构象变化的受体蛋白定义的换能器的选择性。GPCR下游的信号通路选择性尚未完全了解。在这里，作者对卷曲突变体进行功能分析，以揭示状态稳定残基或“微开关”介导对G蛋白的选择性。
The class Frizzled of G protein-coupled receptors (GPCRs), consisting of ten Frizzled (FZD1-10) paralogs and Smoothened, remains one of the most enigmatic GPCR families. This class mediates signaling predominantly through Disheveled (DVL) or heterotrimeric G proteins. However, the mechanisms underlying pathway selection are elusive. Here we employ a structure-driven mutagenesis approach in combination with an extensive panel of functional signaling readouts to investigate the importance of conserved state-stabilizing residues in FZD5 for signal specification. Similar data were obtained for FZD4 and FZD10 suggesting that our findings can be extrapolated to other members of the FZD family. Comparative molecular dynamics simulations of wild type and selected FZD5 mutants further support the concept that distinct conformational changes in FZDs specify the signal outcome. In conclusion, we find that FZD5 and FZDs in general prefer coupling to DVL rather than heterotrimeric G proteins and that distinct active state micro-switches in the receptor are essential for pathway selection arguing for conformational changes in the receptor protein defining transducer selectivity. Signaling pathway selectivity downstream of GPCRs is not fully understood. Here, authors perform functional analysis of Frizzled mutants to uncover state-stabilizing residues or ‘micro-switches’ mediating selectivity towards Disheveled over G proteins.
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影响因子：
4
作者：
Gammons MV;Rutherford TJ;Steinhart Z;Angers S;Bienz M
通讯作者：
Bienz M
DOI：
10.1111/dgd.12718
发表时间：
2021-04
期刊：
Development, growth & differentiation
影响因子：
--
作者：
Colozza G;Koo BK
通讯作者：
Koo BK
DOI：
10.1074/jbc.m114.590638
发表时间：
2014-08-22
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Bernatík O;Šedová K;Schille C;Ganji RS;Červenka I;Trantírek L;Schambony A;Zdráhal Z;Bryja V
通讯作者：
Bryja V
影响因子：
4.8
作者：
Bernatik, Ondrej;Ganji, Ranjani Sri;Bryja, Vitezslav
通讯作者：
Bryja, Vitezslav
影响因子：
16
作者：
Gammons, Melissa V.;Renko, Miha;Johnson, Christopher M.;Rutherford, Trevor J.;Bienz, Mariann
通讯作者：
Bienz, Mariann