Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops.
Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops.
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DOI：
10.1016/j.str.2008.10.010
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发表时间：
2008-12-10
期刊：
影响因子：
--
通讯作者：
Chuang DT
中科院分区：
文献类型：
--
作者：
Kato M;Wynn RM;Chuang JL;Tso SC;Machius M;Li J;Chuang DT
我们报告的晶体结构的磷酸化丙酮酸脱氢酶（E1 p）的组成部分的人丙酮酸脱氢酶复合物（PDC）。使用不含PDC核心的稳健丙酮酸脱氢酶激酶4实现了变体E1 p蛋白的Ser 264-α（位点1）的完全磷酸化。我们发现，与未修饰的对应物不同，Ser 264-α上磷酰基的存在阻止了辅因子二磷酸硫胺素诱导的携带三个磷酸化位点的两个环的有序化。这些磷酸化环的无序化是由位点1的磷酰基和附近的Ser 266-α之间先前未被识别的空间冲突引起的，这使得维持环构象所必需的氢键网络无效。无序的磷酸化环阻碍PDC核心的硫辛酰基结构域与E1 p的结合，从而否定还原乙酰化步骤。这导致PDC中基质通道的破坏，导致该催化机器的失活。
We report the crystal structures of the phosporylated pyruvate dehydrogenase (E1p) component of the human pyruvate dehydrogenase complex (PDC). The complete phosphorylation at Ser264-α (site 1) of a variant E1p protein was achieved using robust pyruvate dehydrogenase kinase 4 free of the PDC core. We show that unlike its unmodified counterpart, the presence of a phosphoryl group at Ser264-α prevents the cofactor thiamine diphosphate-induced ordering of the two loops carrying the three phosphorylation sites. The disordering of these phosphorylation loops is caused by a previously unrecognized steric clash between the phosphoryl group at site 1 and a nearby Ser266-α, which nullifies a hydrogen-bonding network essential for maintaining the loop conformations. The disordered phosphorylation loops impede the binding of lipoyl domains of the PDC core to E1p negating the reductive acetylation step. This results in the disruption of the substrate channeling in the PDC, leading to the inactivation of this catalytic machine.
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影响因子：
4.8
作者：
Harris, RA;BowkerKinley, MM;Popov, KM
通讯作者：
Popov, KM
影响因子：
4.8
作者：
ALI, MS;SHENOY, BC;PATEL, MS
通讯作者：
PATEL, MS
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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通讯作者：
Cowtan, K
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
56.9
作者：
Frank, RAW;Titman, CM;Perham, RN
通讯作者：
Perham, RN