Role of Oligomeric State in HMG-CoA Reductase Degradation

S. K. Sather, H. H. Cheng, H. Kumagai, R. D. Simoni

Research output: Contribution to journalArticle

Abstract

The degradation rate of HMG-CoA reductase (HMGR) is increased by treatment of cells with the regulatory molecules mevalonate and sterols. HMGR's membrane domain is required for this regulated degradation. Fusion of the membrane domain to /3-galactosidase (/3-gal) yields a protein f HMGal) whose degradation is regulated properly by mevalonate and sterols. Because HMGal has a-gal activity, the fusion protein must form functional i?-gal tetramers. Deletions of 10 to 20 amino acids from /3-gal's C-terrninus which prevent tetramerization resul' in loss of regulated degradation of HMGal. Oligomerluation of HMGal via the /3-gal domain and thus HMGR via its cytosolic domain may be necessary for regulated degradation. Regulatory molecules may cause a change in HMGR's oligomeric state, leading to degradation. Fusions of the HMGR membrane domain to the monomeric proteins hygromycin B phosphotransferase, green fluorescent protein, or the HA epitope tag were degraded rapidly and without regulation. However, a fusion to XGPRT protein, which can trimerize, was degraded in a regulated manner. In vivo chemical cross linking with DSG and BSOCOES yielded anti-HMGR reactive complexe o! 205 and 230 kDa (DSG) and 230 and 250 kDa (BSOCOES) which may represent dimers or larger oligomers of the 97 kDa HMGR monomer. Cleavage of BSOCOES cross-linked complexes showed the presence of HMGR monomers within the complexes. Further analysis of cross-linking in cells expressing HMGR fusion proteins or treated with regulatory molecules will provide information on the role of oligomerization in HMGR degradation. (S. K. S. was supported by AHA, California Affiliate.).

Original languageEnglish (US)
Pages (from-to)A1402
JournalFASEB Journal
Volume10
Issue number6
StatePublished - Dec 1 1996

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Sather, S. K., Cheng, H. H., Kumagai, H., & Simoni, R. D. (1996). Role of Oligomeric State in HMG-CoA Reductase Degradation. FASEB Journal, 10(6), A1402.