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Cited by 58Enzyme Structure and FunctionRetinoids in leukemia and cellular processesLipid metabolism and biosynthesis

Lrat-specific domain facilitates Vitamin A metabolism by domain swapping in HRASLS3

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Golczak, Marcin, Sears, Avery E, Kiser, Philip D, Palczewski, Krzysztof·2015·Nature Chemical Biology
DOI 10.1038/nchembio.1687PMC PMC4270908
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Abstract

Cellular uptake of vitamin A, production of visual chromophore and triglyceride homeostasis in adipocytes depend on two representatives of the vertebrate N1pC/P60 protein family, lecithin:retinol acyltransferase (LRAT) and HRAS-like tumor suppressor 3 (HRASLS3). Both proteins function as lipid-metabolizing enzymes but differ in their substrate preferences and dominant catalytic activity. The mechanism of this catalytic diversity is not understood. Here, by using a gain-of-function approach, we identified a specific sequence responsible for the substrate specificity of N1pC/P60 proteins. A 2.2-Å crystal structure of the HRASLS3-LRAT chimeric enzyme in a thioester catalytic intermediate state revealed a major structural rearrangement accompanied by three-dimensional domain swapping dimerization not observed in native HRASLS proteins. Structural changes affecting the active site environment contributed to slower hydrolysis of the catalytic intermediate, supporting efficient acyl transfer. These findings reveal structural adaptation that facilitates selective catalysis and mechanism responsible for diverse substrate specificity within the LRAT-like enzyme family.

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Crossref · 10.1038/nchembio.1687

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  • Unlike native HRASLS, the chimeric protein forms a constitutive homodimer.

    “Unlike native HRASLS, the chimeric protein forms a constitutive homodimer [80,108].”

    From Molecular Basis for Vitamin A Uptake and Storage in Vertebrates (2016) · cites this paper as [80]

    The Results section (“Structural rearrangement induced by LRAT-specific domain”; page not available) says the chimera’s dominant form in solution is a dimer and that, unlike native HRASLS3, it crystallized as a homodimer. It does not establish that dimerization is constitutive rather than simply predominant under the conditions tested. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • All tested chimeric HRASLS/LRAT enzymes, in which the 30-aa LRAT-specific sequence was added to the catalytic domain of HRASLS2, 3 or 4, revealed the ability to transfer the acyl moiety onto vitamin A forming REs.

    “In contrast to the native HRASLS proteins, all of the tested chimeric HRASLS/LRAT enzymes revealed the ability to transfer the acyl moiety onto vitamin A forming REs.”

    From Molecular Basis for Vitamin A Uptake and Storage in Vertebrates (2016) · cites this paper as [80]

  • The crystal structure of the HRASLS3/LRAT chimeric protein provided a mechanistic explanation for the change in substrate specificity.

    “The determination of the crystal structure of HRASLS3/LRAT chimeric protein provided a mechanistic explanation for the remarkable change in substrate specificity [80].”

    From Molecular Basis for Vitamin A Uptake and Storage in Vertebrates (2016) · cites this paper as [80]

  • The LRAT domain folds into an extended β-hairpin motif that imposes profound structural and functional consequences for the enzyme.

    “The LRAT domain folds into an extended β-hairpin motif that imposes profound structural and functional consequences for the enzyme.”

    From Molecular Basis for Vitamin A Uptake and Storage in Vertebrates (2016) · cites this paper as [80]

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Research works printed but not linked: 1

  1. [37]Albalat R Evolution of the Genetic Machinery of the Visual Cycle: A Novelty of the Vertebrate Eye? Mol Biol Evol 2012 29 1461 1469 22319134

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Authors
Golczak, M., Sears, A. E., Kiser, P. D., & Palczewski, K.
Affiliations
Case Western Reserve University (US)
Corresponding author
  • Golczak, Marcin
  • Palczewski, Krzysztof
ORCID
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2014-11-10
Volume
11
Issue
1
Pages
26-32
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
DOI
10.1038/nchembio.1687
PMC
PMC4270908
OpenAlex
W2043863013
Cited by
58
References
58
Citations by year
2026: 2 · 2025: 5 · 2024: 4 · 2023: 7 · 2022: 3 · 2021: 5 · 2020: 8 · 2019: 8 · 2018: 1 · 2017: 6 · 2016: 6 · 2015: 2 · 2014: 1
FWCI
2.27
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Department of Energy (DE‐ AC02‐06CH11357, AC02‐06CH11357, 06CH11357, P41 RR012408, DE-AC02-)
  • National Institutes of Health (DE-AC02–06CH11357, EY009339, GM007250)
  • Office of Science (AC02‐06CH11357, DE-AC02, 06CH11357, DE-AC02-06CH11357)
  • National Eye Institute (EY009339, EY023948, R01EY023948, R01EY009339)
  • National Institute of General Medical Sciences (T32GM007250, P41GM103473, DE-AC02-06CH11357, GM 007250)
  • National Center for Research Resources (P41RR012408)
  • Basic Energy Sciences (DE-AC02, DE-AC- 02-06CH11357, AC02‐06CH11357, 06CH11357)
  • Biological and Environmental Research (DEAC0206CH11357)
  • Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, 06CH11357)
Topics
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
LRAT, vitamin A metabolism, domain swapping, thioester intermediate, substrate specificity, retinol esterification, triglyceride homeostasis, adipocytes
MeSH terms
Acyltransferases, Animals, Humans, Mice, Transgenic, Models, Molecular, Protein Conformation, Substrate Specificity, Vitamin A, Tumor Suppressor Proteins, Retinol O-Fatty-Acyltransferase, Mice, Phospholipases A2, Calcium-Independent

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