title: Hetero-oligomeric interactions of an ELOVL4 mutant protein: implications in the molecular mechanism of Stargardt-3 macular dystrophy.
abstract: OBJECTIVE
  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.affiliation: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Okuda
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Naganuma
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohno
authors.forename: Kensuke
authors.initials: K
authors.lastname: Abe
authors.forename: Maki
authors.initials: M
authors.lastname: Yamagata
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Akio
authors.initials: A
authors.lastname: Kihara
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D025063:Chromosome Disorders / Q000150:complications / Q000378:metabolism; D002896:Chromosomes, Human, Pair 6 / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000378:metabolism; D005136:Eye Proteins / Q000737:chemistry* / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008268:Macular Degeneration / Q000150:complications / Q000378:metabolism* / Q000151:congenital; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D020836:Protein Structure, Quaternary
chemical_list: C418975:ELOVL4 protein, human; D005136:Eye Proteins; D005231:Fatty Acids, Unsaturated; D008565:Membrane Proteins; D050505:Mutant Proteins; D015118:Eicosapentaenoic Acid; D000429:Alcohol Oxidoreductases; C026219:docosapentaenoic acid