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

Abstract

PURPOSE:

Stargardt disease 3 (STGD3) is a juvenile macular dystrophy caused by mutations in the elongase of very long-chain 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 hetero-oligomeric interactions, may contribute to the pathology of STGD3.

• Authors: Ayaka Okuda, Tatsuro Naganuma, Yusuke Ohno, Kensuke Abe, Maki Yamagata, Yasuyuki Igarashi, Akio Kihara
• Journal: Molecular vision (Mol Vis) Vol. 16 Pg. 2438-45 (Nov 18 2010) ISSN: 1090-0535 [Electronic] United States
• PMID: 21139992 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ELOVL4 protein, human
• Eye Proteins
• Fatty Acids, Unsaturated
• Membrane Proteins
• Mutant Proteins
• Eicosapentaenoic Acid
• Alcohol Oxidoreductases
• docosapentaenoic acid

Topics

• Alcohol Oxidoreductases (metabolism)
• Animals
• Chromosome Disorders (complications, metabolism)
• Chromosomes, Human, Pair 6 (metabolism)
• Eicosapentaenoic Acid (metabolism)
• Eye Proteins (chemistry, metabolism)
• Fatty Acids, Unsaturated (metabolism)
• HEK293 Cells
• Humans
• Macular Degeneration (complications, metabolism)
• Membrane Proteins (chemistry, metabolism)
• Metabolic Networks and Pathways
• Mice
• Mutant Proteins (chemistry, metabolism)
• Protein Binding
• Protein Structure, Quaternary