Mark A. Lehrman
Department of Pharmacology
University of Texas Southwestern Medical Center
5323 Harry Hines Blvd.
Dallas, TX 75235
1987 Searle Scholar
Glycoconjugates are carbohydrates that are covalently bound to proteins or lipids, and they perform many important biological roles. Our laboratory employs biochemical, genetic, and molecular biological methods to explore the biosynthesis and functions of glycoconjugates in three separate projects.
1) GPT (GlcNAc-1-P transferase) is a membrane-associated endoplasmic reticulum (ER) enzyme which initiates the biosynthesis of a class of glycoconjugate (termed "N-linked") in which carbohydrates are coupled to asparagine residues of secretory and membrane proteins. We have cloned mammalian GPT and have shown that is an atypical glycosyltransferase in that it spans the ER membrane multiple times. Recent data indicate that GPT may be directly involved in regulation of N-glycan synthesis.
2) Chaperones assist in protein folding, and at least two chaperones (calnexin and calreticulin) bind to unfolded proteins which have a specific kind of N-linked carbohydrate called Glc1Man9GlcNAc2. We demonstrated that these chaperones bind directly to the carbohydrate. Our laboratory is now engaged in an examination of the gene products involved in assembly of this carbohydrate. Along these lines we have recently cloned (by functional expression) a novel protein, possibly and enzyme, which is involved.
3) GPI-anchored proteins are extracellular proteins linked to membrane-bound phosphatidylinositol via a carbohydrate "stalk". These stalks are decorated in a cell- and tissue-specific manner with other carbohydrates, but the functions of the decorations are unknown. For this reason, we have recently begun an investigation of the biosynthesis and structural variations of these decorations. In addition, GPI anchors are transiently modified with a palmitate residue. We have recently designed a system to study the biochemistry and function of the palmitate in detail.
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