Mutations Causing Slow-Channel Myasthenia Reveal That a Valine Ring in the Channel Pore of Muscle AChR is Optimized for Stabilizing Channel Gating.
Mutations Causing Slow-Channel Myasthenia Reveal That a Valine Ring in the Channel Pore of Muscle AChR is Optimized for Stabilizing Channel Gating.
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DOI：
10.1002/humu.23043
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发表时间：
2016-10
期刊：
影响因子：
3.9
通讯作者：
Engel, Andrew G.
中科院分区：
文献类型：
--
作者：
Shen, Xin-Ming;Okuno, Tatsuya;Milone, Margherita;Otsuka, Kenji;Takahashi, Koji;Komaki, Hirofumi;Giles, Elizabeth;Ohno, Kinji;Engel, Andrew G.
关键词：
我们确定了两个新的突变乙酰胆碱受体（AChR）引起的慢通道先天性肌无力综合征（CMS）在三个无关的患者（Pts）。Pt 1在AChR β亚基（CHRNB1）的第二跨膜区（M2）中存在一个杂合性βV266A突变（p.Val289Ala）。患者2和3在ε亚基（CHRNE）的等同位点εV265A（p.Val285Ala）携带相同突变。突变残基在所有物种的所有AChR亚基中是保守的，并且是位于亮氨酸环上方四个残基的通道孔中的缬氨酸环的组分。β V266 A和ε V265 A均通过将门控效率提高约30倍来减小氨基酸大小并将通道开放爆发延长4.0倍。在δ和α亚基的相应位置用丙氨酸取代缬氨酸，爆发持续时间分别延长4倍和8倍。用更小的甘氨酸或更大的亮氨酸替换ε密码子265处的缬氨酸也会延长爆发持续时间。我们的分析表明，每个缬氨酸在缬氨酸环通道动力学的贡献相等，和缬氨酸环已被优化的过程中的演变，以管理通道门控。
We identify two novel mutations in acetylcholine receptor (AChR) causing a slow-channel congenital myasthenia syndrome (CMS) in three unrelated patients (Pts). Pt 1 harbors a heterozygous βV266A mutation (p.Val289Ala) in the second transmembrane domain (M2) of the AChR β subunit (CHRNB1). Pts 2 and 3 carry the same mutation at an equivalent site in the ε subunit (CHRNE), εV265A (p.Val285Ala). The mutant residues are conserved across all AChR subunits of all species and are components of a valine ring in the channel pore which is positioned four residues above the leucine ring. Both βV266A and εV265A reduce the amino acid size and lengthen the channel opening bursts by 4.0-fold by enhancing gating efficiency by approximately 30-fold. Substitution of alanine for valine at the corresponding position in the δ and α subunit prolongs the burst duration 4- and 8-fold, respectively. Replacing valine at ε codon 265 either by a still smaller glycine or by a larger leucine also lengthens the burst duration. Our analysis reveals that each valine in the valine ring contributes to channel kinetics equally, and the valine ring has been optimized in the course of evolution to govern channel gating.
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DOI：
10.1073/pnas.92.3.758
发表时间：
1995-01-31
影响因子：
11.1
作者：
OHNO, K;HUTCHINSON, DO;ENGEL, AG
通讯作者：
ENGEL, AG
影响因子：
5.5
作者：
Fucile, Sergio;Sucapane, Antonietta;Engel, Andrew G.
通讯作者：
Engel, Andrew G.
影响因子：
2.8
作者：
Fidzianska, A;Ryniewicz, B;Engel, AG
通讯作者：
Engel, AG
DOI：
10.1111/j.1749-6632.1998.tb10929.x
发表时间：
1998-01-01
期刊：
MYASTHENIA GRAVIS AND RELATED DISEASES
影响因子：
--
作者：
Harper, CM;Engel, AG
通讯作者：
Engel, AG
影响因子：
14.5
作者：
Shen, XM;Ohno, K;Engel, AG
通讯作者：
Engel, AG