Structure of RPE65 isomerase in a lipidic matrix reveals roles for phospholipids and iron in catalysis
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RPE65 is a key metalloenzyme responsible for maintaining visual function in vertebrates. Despite extensive research on this membrane-bound retinoid isomerase, fundamental questions regarding its enzymology remain unanswered. Here, we report the crystal structure of RPE65 in a membrane-like environment. These crystals, obtained from enzymatically active, nondelipidated protein, displayed an unusual packing arrangement wherein RPE65 is embedded in a lipid–detergent sheet. Structural differences between delipidated and nondelipidated RPE65 uncovered key residues involved in substrate uptake and processing. Complementary iron K-edge X-ray absorption spectroscopy data established that RPE65 as isolated contained a divalent iron center and demonstrated the presence of a tightly bound ligand consistent with a coordinated carboxylate group. These results support the hypothesis that the Lewis acidity of iron could be used to promote ester dissociation and generation of a carbocation intermediate required for retinoid isomerization.
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The structure of RPE65 provided an incentive for obtaining structures of other membrane-associated proteins including LRAT and RDHs.
“The structure of RPE65452,455 definitely provided an incentive for obtaining structures of other membrane associated proteins including LRAT and RDHs.”
From Chemistry of the Retinoid (Visual) Cycle (2014) · cites this paper as [455]
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- Authors
- Kiser, P. D., Farquhar, E. R., Shi, W., Sui, X., Chance, M. R., & Palczewski, K.
- Affiliations
- Case Western Reserve University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-09-24
- Volume
- 109
- Issue
- 41
- Pages
- E2747-56
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3478654
- OpenAlex
- W2090239623
- Cited by
- 63
- References
- 67
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 6 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 10 · 2019: 5 · 2018: 5 · 2017: 2 · 2016: 3 · 2015: 9 · 2014: 5 · 2013: 8
- FWCI
- 3.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Case Western Reserve University
- Albert-Ludwigs-Universität Freiburg
- National Institutes of Health (EY011373)
- National Eye Institute (EY020551, EY009339, R01EY020551, P30EY011373, R01EY009339)
- National Institute of General Medical Sciences (P41GM103403)
- National Institute of Biomedical Imaging and Bioengineering (P30EB009998)
- National Center for Research Resources (P41RR015301)
- Topics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Photoreceptor and optogenetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- RPE65, crystal structure, membrane proteins, phospholipids, iron, carboxylate ligands, Lewis acidity, carbocation intermediates, visual function, substrate binding
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Catalysis, Cattle, Iron, Lipids, Microsomes, Models, Molecular, Molecular Sequence Data, Phospholipids, Protein Conformation, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Crystallography, X-Ray, cis-trans-Isomerases, Retinal Pigment Epithelium, X-Ray Absorption Spectroscopy
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