دورية أكاديمية
Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency
| العنوان: | Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency |
|---|---|
| المؤلفون: | Prew, Michelle S., Camara, Christina M., Botzanowski, Thomas, Moroco, Jamie A., Bloch, Noah B., Levy, Hannah R., Seo, Hyuk-Soo, Dhe-Paganon, Sirano, Bird, Gregory H., Herce, Henry D., Gygi, Micah A., Escudero, Silvia, Wales, Thomas E., Engen, John R., Walensky, Loren D. |
| المساهمون: | U.S. Department of Health & Human Services | National Institutes of Health, U.S. Department of Health & Human Services | NIH | National Cancer Institute |
| المصدر: | Nature Communications ; volume 13, issue 1 ; ISSN 2041-1723 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41467-022-31466-2 |
| الإتاحة: | https://doi.org/10.1038/s41467-022-31466-2Test https://www.nature.com/articles/s41467-022-31466-2.pdfTest https://www.nature.com/articles/s41467-022-31466-2Test |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.592B5B28 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-022-31466-2 |
|---|