Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency.
Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency.
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DOI：
10.1038/s41467-022-31466-2
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发表时间：
2022-06-27
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
甚长链酰基辅酶a脱氢酶（VLCAD）是一种线粒体内膜酶，催化长链脂肪酸氧化的第一步和限速步骤。人类VLCAD的点突变可产生先天性代谢错误，称为VLCAD缺乏症，可导致严重的病理生理后果，包括心肌病、低血糖和横纹肌溶解。VLCAD的c端结构域区域的离散突变通过不完全确定的机制引起酶缺陷。在这里，我们进行了结构-功能研究，结合x射线晶体学，氢-氘交换质谱，计算模型和生化分析，来表征全长的特定膜相互作用缺陷，人类VLCAD携带临床观察到的突变，A450P或L462P。通过破坏预测的α-螺旋发夹，这些突变部分或完全破坏了与膜本身的直接相互作用。因此，我们的数据支持了α-螺旋膜结合基序离散突变患者VLCAD缺陷的结构基础，导致病理性酶错定位。Prew等人发现了人类VLCAD缺陷的结构基础，这种缺陷是由酶的膜结合区域内的点突变引起的，该区域被证明可以折叠成假定的α-螺旋发夹。螺旋断裂突变选择性地破坏膜相互作用，从而破坏稳态功能。
Very long-chain acyl-CoA dehydrogenase (VLCAD) is an inner mitochondrial membrane enzyme that catalyzes the first and rate-limiting step of long-chain fatty acid oxidation. Point mutations in human VLCAD can produce an inborn error of metabolism called VLCAD deficiency that can lead to severe pathophysiologic consequences, including cardiomyopathy, hypoglycemia, and rhabdomyolysis. Discrete mutations in a structurally-uncharacterized C-terminal domain region of VLCAD cause enzymatic deficiency by an incompletely defined mechanism. Here, we conducted a structure-function study, incorporating X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, computational modeling, and biochemical analyses, to characterize a specific membrane interaction defect of full-length, human VLCAD bearing the clinically-observed mutations, A450P or L462P. By disrupting a predicted α-helical hairpin, these mutations either partially or completely impair direct interaction with the membrane itself. Thus, our data support a structural basis for VLCAD deficiency in patients with discrete mutations in an α-helical membrane-binding motif, resulting in pathologic enzyme mislocalization. Prew et al. uncovered a structural basis for human VLCAD deficiency that arises from point mutations within the enzyme’s membrane-binding region, which was shown to fold as a putative α-helical hairpin. Helix-breaking mutations selectively disrupt membrane interaction and thus homeostatic function.
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影响因子：
16
作者：
Barclay, Lauren A.;Wales, Thomas E.;Garner, Thomas P.;Wachter, Franziska;Lee, Susan;Guerra, Rachel M.;Stewart, Michelle L.;Braun, Craig R.;Bird, Gregory H.;Gavathiotis, Evripidis;Engen, John R.;Walensky, Loren D.
通讯作者：
Walensky, Loren D.
氢/氘交换MS对蛋白质构象和动力学的分析。
影响因子：
7.4
作者：
Engen, John R.
通讯作者：
Engen, John R.
影响因子：
4.4
作者：
FELLER, SE;ZHANG, YH;BROOKS, BR
通讯作者：
BROOKS, BR
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG
DOI：
10.1063/1.5036677
发表时间：
2018-07-21
期刊：
The Journal of chemical physics
影响因子：
--
作者：
Elenewski JE;Velizhanin KA;Zwolak M
通讯作者：
Zwolak M