Insertion and topology of normal and mutant bestrophin-1 in the endoplasmic reticulum membrane.

Abstract	The vitelliform macular dystrophy type 2 (VMD2) gene mutated in Best macular dystrophy encodes a 585-amino acid putative transmembrane protein termed bestrophin-1. The vast majority of known disease-associated alterations are of the missense type, which cluster near predicted transmembrane domains (TMDs). To investigate bestrophin-1 membrane topology and to assess consequences of point mutations on membrane integration, we have analyzed the insertion of putative TMDs into the endoplasmic reticulum (ER) membrane. Out of six potential TMDs, our data suggest a topological model of bestrophin-1 with four transmembrane-spanning segments and one large cytoplasmatic loop between putative TMD2 and TMD5. Consequently, a relatively hydrophobic segment containing putative TMD3 (aa 130-149) and TMD4 (aa 179-201) is located within the cytoplasm. Furthermore, we show that three out of 18 disease-associated alterations investigated (I73N, Y85H, F281del) reveal measurable effects on membrane insertion suggesting that defective membrane integration of bestrophin-1 may represent a potential disease mechanism for a small subset of Best macular dystrophy-related mutations.
Authors	Vladimir M Milenkovic, Andrea Rivera, Franziska Horling, Bernhard H F Weber
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 2 Pg. 1313-21 (Jan 12 2007) ISSN: 0021-9258 [Print] United States
PMID	17110374 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	BEST1 protein, human Bestrophins Chloride Channels Eye Proteins Membrane Proteins
Topics	Animals Bestrophins Chloride Channels Corneal Dystrophies, Hereditary (genetics, metabolism) Endoplasmic Reticulum (metabolism) Eye Proteins (chemistry, genetics, metabolism) Humans Hydrophobic and Hydrophilic Interactions Membrane Proteins (chemistry, genetics, metabolism) Phylogeny Point Mutation Protein Structure, Tertiary

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