Hetero-oligomeric interactions of an ELOVL4 mutant protein: Implications in the molecular mechanism of Stargardt-3 macular dystrophy

Ayaka Okuda, Tatsuro Naganuma, Yusuke Ohno, Kensuke Abe, Maki Yamagata, Yasuyuki Igarashi, Akio Kihara

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Purpose: Stargardt disease 3 (STGD3) is a juvenile macular dystrophy caused by mutations in the elongase of very longchain fatty acids-like 4 (ELOVL4) gene, which encodes an elongase involved in the production of extremely long-chain fatty acids. The STGD3-related mutations cause production of C-terminally truncated proteins (ELOVL4ΔC). STGD3 is transmitted in an autosomal dominant manner. To date, molecular mechanisms of this pathology have been proposed based solely on the interaction between wild-type ELOVL4 and ELOVL4ΔC. However, analyses of Elovl4ΔC knockin mice revealed reduced levels of not only ELOVL4 substrates, but also of fatty acids with a broad spectrum of chain lengths. Therefore, we investigated the molecular mechanisms responsible for ELOVL4ΔC affecting the entire very long-chain fatty acid (VLCFA) elongation pathway. Methods: The ELOVL4ΔC protein was expressed in HEK 293T cells, and its effect on elongase activities toward several acyl-CoAs were examined. We also investigated the homo- and hetero-oligomerization of ELOVL4ΔC with other elongases (ELOVL1-7) or with other enzymes involved in VLCFA elongation using coimmunoprecipitation experiments. Results: We found that ELOVL4ΔC forms a homo-oligomer more strongly than wild-type ELOVL4. ELOVL4ΔC also interacts strongly with other elongases, although similar interactions for wild-type ELOVL4 were observed as only weak. In addition, ELOVL4ΔC is able to form an elongase complex by interacting with other components of the VLCFA elongation machinery, similar to wild-type ELOVL4. Conclusions: We propose that not only the ELOVL4-ELOVL4ΔC homo-oligomeric interaction, but also several heterooligomeric interactions, may contribute to the pathology of STGD3.

Original languageEnglish
Pages (from-to)2438-2445
Number of pages8
JournalMolecular Vision
Volume16
Publication statusPublished - 2010
Externally publishedYes

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Macular Degeneration
Mutant Proteins
Fatty Acids
Mutation
Molecular Pathology
HEK293 Cells
Proteins
Pathology
Stargardt disease 3
Enzymes
Genes

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Hetero-oligomeric interactions of an ELOVL4 mutant protein : Implications in the molecular mechanism of Stargardt-3 macular dystrophy. / Okuda, Ayaka; Naganuma, Tatsuro; Ohno, Yusuke; Abe, Kensuke; Yamagata, Maki; Igarashi, Yasuyuki; Kihara, Akio.

In: Molecular Vision, Vol. 16, 2010, p. 2438-2445.

Research output: Contribution to journalArticle

Okuda, Ayaka ; Naganuma, Tatsuro ; Ohno, Yusuke ; Abe, Kensuke ; Yamagata, Maki ; Igarashi, Yasuyuki ; Kihara, Akio. / Hetero-oligomeric interactions of an ELOVL4 mutant protein : Implications in the molecular mechanism of Stargardt-3 macular dystrophy. In: Molecular Vision. 2010 ; Vol. 16. pp. 2438-2445.
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abstract = "Purpose: Stargardt disease 3 (STGD3) is a juvenile macular dystrophy caused by mutations in the elongase of very longchain fatty acids-like 4 (ELOVL4) gene, which encodes an elongase involved in the production of extremely long-chain fatty acids. The STGD3-related mutations cause production of C-terminally truncated proteins (ELOVL4ΔC). STGD3 is transmitted in an autosomal dominant manner. To date, molecular mechanisms of this pathology have been proposed based solely on the interaction between wild-type ELOVL4 and ELOVL4ΔC. However, analyses of Elovl4ΔC knockin mice revealed reduced levels of not only ELOVL4 substrates, but also of fatty acids with a broad spectrum of chain lengths. Therefore, we investigated the molecular mechanisms responsible for ELOVL4ΔC affecting the entire very long-chain fatty acid (VLCFA) elongation pathway. Methods: The ELOVL4ΔC protein was expressed in HEK 293T cells, and its effect on elongase activities toward several acyl-CoAs were examined. We also investigated the homo- and hetero-oligomerization of ELOVL4ΔC with other elongases (ELOVL1-7) or with other enzymes involved in VLCFA elongation using coimmunoprecipitation experiments. Results: We found that ELOVL4ΔC forms a homo-oligomer more strongly than wild-type ELOVL4. ELOVL4ΔC also interacts strongly with other elongases, although similar interactions for wild-type ELOVL4 were observed as only weak. In addition, ELOVL4ΔC is able to form an elongase complex by interacting with other components of the VLCFA elongation machinery, similar to wild-type ELOVL4. Conclusions: We propose that not only the ELOVL4-ELOVL4ΔC homo-oligomeric interaction, but also several heterooligomeric interactions, may contribute to the pathology of STGD3.",
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T1 - Hetero-oligomeric interactions of an ELOVL4 mutant protein

T2 - Implications in the molecular mechanism of Stargardt-3 macular dystrophy

AU - Okuda, Ayaka

AU - Naganuma, Tatsuro

AU - Ohno, Yusuke

AU - Abe, Kensuke

AU - Yamagata, Maki

AU - Igarashi, Yasuyuki

AU - Kihara, Akio

PY - 2010

Y1 - 2010

N2 - Purpose: Stargardt disease 3 (STGD3) is a juvenile macular dystrophy caused by mutations in the elongase of very longchain fatty acids-like 4 (ELOVL4) gene, which encodes an elongase involved in the production of extremely long-chain fatty acids. The STGD3-related mutations cause production of C-terminally truncated proteins (ELOVL4ΔC). STGD3 is transmitted in an autosomal dominant manner. To date, molecular mechanisms of this pathology have been proposed based solely on the interaction between wild-type ELOVL4 and ELOVL4ΔC. However, analyses of Elovl4ΔC knockin mice revealed reduced levels of not only ELOVL4 substrates, but also of fatty acids with a broad spectrum of chain lengths. Therefore, we investigated the molecular mechanisms responsible for ELOVL4ΔC affecting the entire very long-chain fatty acid (VLCFA) elongation pathway. Methods: The ELOVL4ΔC protein was expressed in HEK 293T cells, and its effect on elongase activities toward several acyl-CoAs were examined. We also investigated the homo- and hetero-oligomerization of ELOVL4ΔC with other elongases (ELOVL1-7) or with other enzymes involved in VLCFA elongation using coimmunoprecipitation experiments. Results: We found that ELOVL4ΔC forms a homo-oligomer more strongly than wild-type ELOVL4. ELOVL4ΔC also interacts strongly with other elongases, although similar interactions for wild-type ELOVL4 were observed as only weak. In addition, ELOVL4ΔC is able to form an elongase complex by interacting with other components of the VLCFA elongation machinery, similar to wild-type ELOVL4. Conclusions: We propose that not only the ELOVL4-ELOVL4ΔC homo-oligomeric interaction, but also several heterooligomeric interactions, may contribute to the pathology of STGD3.

AB - Purpose: Stargardt disease 3 (STGD3) is a juvenile macular dystrophy caused by mutations in the elongase of very longchain fatty acids-like 4 (ELOVL4) gene, which encodes an elongase involved in the production of extremely long-chain fatty acids. The STGD3-related mutations cause production of C-terminally truncated proteins (ELOVL4ΔC). STGD3 is transmitted in an autosomal dominant manner. To date, molecular mechanisms of this pathology have been proposed based solely on the interaction between wild-type ELOVL4 and ELOVL4ΔC. However, analyses of Elovl4ΔC knockin mice revealed reduced levels of not only ELOVL4 substrates, but also of fatty acids with a broad spectrum of chain lengths. Therefore, we investigated the molecular mechanisms responsible for ELOVL4ΔC affecting the entire very long-chain fatty acid (VLCFA) elongation pathway. Methods: The ELOVL4ΔC protein was expressed in HEK 293T cells, and its effect on elongase activities toward several acyl-CoAs were examined. We also investigated the homo- and hetero-oligomerization of ELOVL4ΔC with other elongases (ELOVL1-7) or with other enzymes involved in VLCFA elongation using coimmunoprecipitation experiments. Results: We found that ELOVL4ΔC forms a homo-oligomer more strongly than wild-type ELOVL4. ELOVL4ΔC also interacts strongly with other elongases, although similar interactions for wild-type ELOVL4 were observed as only weak. In addition, ELOVL4ΔC is able to form an elongase complex by interacting with other components of the VLCFA elongation machinery, similar to wild-type ELOVL4. Conclusions: We propose that not only the ELOVL4-ELOVL4ΔC homo-oligomeric interaction, but also several heterooligomeric interactions, may contribute to the pathology of STGD3.

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