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Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency
Nature Communications ( IF 14.7 ) Pub Date : 2022-06-27 , DOI: 10.1038/s41467-022-31466-2
Michelle S Prew 1, 2 , Christina M Camara 1, 2 , Thomas Botzanowski 3 , Jamie A Moroco 3 , Noah B Bloch 1, 2 , Hannah R Levy 1, 2 , Hyuk-Soo Seo 2, 4 , Sirano Dhe-Paganon 2, 4 , Gregory H Bird 1, 2 , Henry D Herce 1, 2 , Micah A Gygi 1, 2 , Silvia Escudero 1, 2 , Thomas E Wales 3 , John R Engen 3 , Loren D Walensky 1, 2
Affiliation  

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.

中文翻译:

人类 VLCAD 缺陷中突变酶的缺陷膜靶向的结构基础

极长链酰基辅酶A脱氢酶(VLCAD)是一种线粒体内膜酶,可催化长链脂肪酸氧化的第一步和限速步骤。人类 VLCAD 的点突变可产生一种称为 VLCAD 缺陷的先天性代谢错误,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症。VLCAD 结构未表征的 C 端结构域区域中的离散突变通过不完全确定的机制导致酶缺乏。在这里,我们进行了一项结构功能研究,结合了 X 射线晶体学、氢-氘交换质谱、计算模型和生化分析,以表征带有临床观察到的突变的全长人类 VLCAD 的特定膜相互作用缺陷、A450P 或 L462P。通过破坏预测的 α-螺旋发夹,这些突变部分或完全损害与膜本身的直接相互作用。因此,我们的数据支持 α-螺旋膜结合基序离散突变患者 VLCAD 缺陷的结构基础,导致病理性酶错误定位。普鲁等人。发现了人类 VLCAD 缺陷的结构基础,该缺陷是由酶膜结合区域内的点突变引起的,该区域被证明折叠为假定的 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。我们的数据支持 α-螺旋膜结合基序离散突变患者 VLCAD 缺陷的结构基础,导致病理性酶错误定位。普鲁等人。发现了人类 VLCAD 缺陷的结构基础,该缺陷是由酶膜结合区域内的点突变引起的,该区域被证明折叠为假定的 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。我们的数据支持 α-螺旋膜结合基序离散突变患者 VLCAD 缺陷的结构基础,导致病理性酶错误定位。普鲁等人。发现了人类 VLCAD 缺陷的结构基础,该缺陷是由酶膜结合区域内的点突变引起的,该区域被证明折叠为假定的 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。
更新日期:2022-06-27
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