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Protein-lipid inter...
Protein-lipid interactions of human dihydroorotate dehydrogenase and three mutants associated with Miller syndrome
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- Orozco Rodriguez, Juan Manuel (författare)
- Lund University,Lunds universitet,Molekylär cellbiologi,Biologiska institutionen,Naturvetenskapliga fakulteten,Molecular Cell Biology,Department of Biology,Faculty of Science
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- Wacklin-Knecht, Hanna (författare)
- Lund University,Lunds universitet,Fysikalisk kemi,Enheten för fysikalisk och teoretisk kemi,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Physical Chemistry,Physical and theoretical chemistry,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH,European Spallation Source ERIC, Sweden
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- Knecht, Wolfgang (författare)
- Lund University,Lunds universitet,Molekylär cellbiologi,Biologiska institutionen,Naturvetenskapliga fakulteten,Molecular Cell Biology,Department of Biology,Faculty of Science
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(creator_code:org_t)
- 2022-02-20
- 2022
- Engelska.
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Ingår i: Nucleosides, Nucleotides & Nucleic Acids. - : Informa UK Limited. - 1525-7770 .- 1532-2335. ; 41:12, s. 1337-1358
- Relaterad länk:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Human dihydroorotate dehydrogenase (DHODH) catalyzes the fourth step of the de novo pyrimidine biosynthesis pathway and uses ubiquinone Q10, a lipophilic molecule located in the inner mitochondrial membrane (IMM), as its co-substrate. DHODH is anchored to the IMM by a single transmembrane helix located at its N-terminus. Nevertheless, how DHODH function is determined by its surrounding membrane environment and protein-lipid interactions, as well as the mechanism by which ubiquinone Q10 accesses the active site of DHODH from within the membrane are still largely unknown. Here, we describe the interaction between wild-type DHODH and three DHODH mutants associated with Miller syndrome and lipids using enzymatic assays, thermal stability assays and Quartz Crystal Microbalance with Dissipation monitoring (QCM-D). Our results provide evidence indicating that the N-terminal part of human DHODH is not only a structural element for mitochondrial import and location of DHODH, but also influences enzymatic activity and utilization of ubiquinone Q10 and ubiquinone analogues in in vitro assays. They also support the role of tetraoleoyl cardiolipin as a lipid interacting with DHODH. Additionally, the results from QCM-D show that the Miller syndrome mutants studied differ in their interactions with supported lipid bilayers compared to wild-type DHODH. These altered interactions add another dimension to the effects of mutations found in Miller syndrome. To the best of our knowledge, this is the first investigation of the protein-lipid interactions of DHODH variants associated with Miller syndrome.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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