Heterodimer formation and activity in the human enzyme galactose-1-phosphate uridylyltransferase.

One of the fundamental questions concerning expression and function of dimeric enzymes involves the impact of naturally occurring mutations on subunit assembly and heterodimer activity. This question is of particular interest for the human enzyme galactose-l-phosphate uridylyl-transferase (GALT), impairment of which results in the inherited metabolic disorder galactosemia, because many if not most patients studied to date are compound heterozygotes rather than true molecular homozygotes. Furthermore, the broad range of phenotypic severity observed in these patients raises the possibility that allelic combination, not just allelic constitution, may play some role in determining outcome. In the work described herein, we have selected two distinct naturally occurring null mutations of GALT, Q188R and R333W, and asked the questions (i) what are the impacts of these mutations on subunit assembly, and (ii) if heterodimers do form, are they active? To answer these questions, we have established a yeast system for the coexpression of epitope-tagged alleles of human GALT and investigated both the extent of specific GALT subunit interactions and the activity of defined heterodimer pools. We have found that both homodimers and heterodimers do form involving each of the mutant subunits tested and that both heterodimer pools retain substantial enzymatic activity. These results are significant not only in terms of their implications for furthering our understanding of galactosemia and GALT holoenzyme structure-function relationships but also because the system described may serve as a model for similar studies of other complexes composed of multiple subunits.

Istanbul, Turkey, 1882 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Plan von Constantinopel mit den Vorstädten, dem Hafen, und einem Theile des Bosporus = Plan de Constantinople avec ses faubourgs, le port et une partie du Bosphore, aufgenommen und gezeichnet von C. Stolpe nach den zeitherigen Veränderungen berichtigt bis zum Jahre 1882. It was published by Verlag von Lorentz & Keil in 1882. Scale 1:15,000. Covers Istanbul, Turkey. Map in German and French.The image inside the map neatline is georeferenced to the surface of the earth and fit to the 'European Datum 1950 UTM Zone 35N' coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map.This map shows features such as roads, railroads and stations, drainage, built-up areas (by ethnicity) and selected buildings, fortification, ground cover, parks, cemeteries, ruins, and more. Relief shown pictorially and by contours.This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.