My research group studies how newly-synthesized polypeptide chains are translocated across biological membranes, fold into their native conformation and are transported to their final cellular localization. Molecular chaperones are required for all these processes but the mechanisms by which they exert their functions are poorly understood. Our experimental strategies involve a variety of molecular and structural approaches to address the following questions: Does peptide specificity of the molecular chaperones determine their functional roles in protein translocation and folding? How are the different activities regulated? What is the role played by posttranslational modifications in the structure/function relationship of molecular chaperones? Our model chaperone is a heat shock protein localized in the endoplasmic reticulum that is known to play an important role in the secretion of all immunoglobulins: the heavy chain immunoglobulin Binding Protein, or BiP. We have performed a detailed analysis of BiP peptide binding specificity and have identified a consensus motif specifically recognized by BiP. We are now in the process of mapping the substrate binding site. Our future goals include the use of protein engineering to alter BiP specificity to allow binding and delivery of peptides relevant for therapeutic needs.
Publications:
1. S. Blond-Elguindi, A.M. Fourie, J.F. Sambrook & M.J. Gething (1993). Peptide-dependent stimulation of the ATPase activity of BiP is the result of conversion of oligomers to active monomer. J. Biol. Chem. 268, 12730-12735.
2. S. Blond-Elguindi. Protein folding in vivo (1993). The role of molecular chaperones in translocation and secretion (French). Les Cahiers IMABIO du C.N.R.S. 8, 49-55.
3. S. Blond-Elguindi, S.E. Cwirla, W.J. Dower, R.J. Lipshutz, S.R. Sprang, J.F. Sambrook and M.J. Gething (1993). Affinity panning of a library of peptides displayed on bacteriophages reveals the binding specificity of BiP. Cell 75, 717-728.
4. M.J. Gething, S. Blond-Elguindi, K. Mori and J.F. Sambrook (1994). Structure, function and regulation of the ER chaperone, BiP. In The biology of heat shock proteins and molecular chaperones . 111-135. Cold Spring Harbor Press, New York.