Transient receptor potential canonical type 6 (TRPC6) O-GlcNAcylation at Threonine-221 plays potent role in channel regulation.
Transient receptor potential canonical type 6 (TRPC6) O-GlcNAcylation at Threonine-221 plays potent role in channel regulation.
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DOI：
10.1016/j.isci.2023.106294
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发表时间：
2023-03-17
期刊：
影响因子：
5.8
通讯作者：
Kass, David A.
中科院分区：
文献类型：
--
作者：
Mishra, Sumita;Ma, Junfeng;McKoy, Desirae;Sasaki, Masayuki;Farinelli, Federica;Page, Richard C.;Ranek, Mark J.;Zachara, Natasha;Kass, David A.
瞬时受体电位典型6型（TRPC 6）是一种主要传导钙离子的非电压门控通道。升高的通道活化有助于纤维化、肥大和蛋白尿，通常与活化的T细胞的核因子（NFAT）的刺激偶联。TRPC 6在糖尿病后受到调节，但O-连接的β-N-乙酰葡糖胺（O-GlcNAc化）在糖尿病中的作用尚不清楚。在这里，我们显示TRPC 6在N-末端锚蛋白-4（AR 4）和接头（LH 1）结构域中的Ser 14、Thr 70和Thr 221处组成性地O-GlcNAc化。丙氨酸的突变揭示了T221作为静息TRPC 6电导的关键控制器，以及相关的NFAT活性和促肥大信号传导。在密切相关的TRPC 3和TRPC 7中同源位点的T→A突变也增加了它们的活性。分子模型预测Thr 221-O-GlcNAc和Ser 199，Glu 200和Glu 246之间的相互作用，后者的组合丙氨酸取代类似地提高静息NFAT活性。因此，正常的TRPC 6通道电导和NFAT激活需要O-GlcNAc酰化的T221以及与配位残基的相互作用。TRPC 6在T221处被组成型O-GlcNAc酰化以抑制基础电导A T221 A突变体TRPC 6具有更大的电导和NFAT活化降低但不升高O-GlcNAc改变T221依赖性TRPC 6功能T221与S199、E200和E246协调以控制基础通道活性生物化学;细胞生理学;细胞生物学
Transient receptor potential canonical type 6 (TRPC6) is a non-voltage-gated channel that principally conducts calcium. Elevated channel activation contributes to fibrosis, hypertrophy, and proteinuria, often coupled to stimulation of nuclear factor of activated T-cells (NFAT). TRPC6 is post-translationally regulated, but a role for O-linked β-N-acetyl glucosamine (O-GlcNAcylation) as elevated by diabetes, is unknown. Here we show TRPC6 is constitutively O-GlcNAcylated at Ser14, Thr70, and Thr221 in the N-terminus ankryn-4 (AR4) and linker (LH1) domains. Mutagenesis to alanine reveals T221 as a critical controller of resting TRPC6 conductance, and associated NFAT activity and pro-hypertrophic signaling. T→A mutations at sites homologous in closely related TRPC3 and TRPC7 also increases their activity. Molecular modeling predicts interactions between Thr221-O-GlcNAc and Ser199, Glu200, and Glu246, and combined alanine substitutions of the latter similarly elevates resting NFAT activity. Thus, O-GlcNAcylated T221 and interactions with coordinating residues is required for normal TRPC6 channel conductance and NFAT activation. TRPC6 is constitutively O-GlcNAcylated at T221 to suppress basal conductance A T221A mutant TRPC6 has much greater conductance and NFAT-activation Reducing but not raising O-GlcNAc alters T221-dependent TRPC6 function T221 coordinates with S199, E200, and E246 to control basal channel activity Biochemistry; Cellular physiology; Cell biology
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影响因子：
5
作者：
Koitabashi N;Aiba T;Hesketh GG;Rowell J;Zhang M;Takimoto E;Tomaselli GF;Kass DA
通讯作者：
Kass DA
DOI：
10.1002/prot.340170405
发表时间：
1993-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
BORK, P
通讯作者：
BORK, P
影响因子：
4.8
作者：
Hisatsune, C;Kuroda, Y;Mikoshiba, K
通讯作者：
Mikoshiba, K
影响因子：
5.5
作者：
Harraz, Osama F.;Jensen, Lars Jorn
通讯作者：
Jensen, Lars Jorn
蛋白O-Glcnacylation：细胞对应激反应的关键调节剂。
影响因子：
--
作者：
Chatham JC;Marchase RB
通讯作者：
Marchase RB