Dr. Armando Parodi
Instituto Fundación Leloir

Glycoprotein synthesis

“Conformational diseases” are caused by protein misfolding and aggregation. Examples of these diseases are amyloidoses, such as immunoglobulin light chain amyloidosis and Alzheimer's disease, Huntington's disease, Parkinson's disease, adult-onset diabetes, cirrhosis, emphysema, and the prion diseases (e.g. mad cow disease). Some of these diseases, such as diabetes, have higher prevalence among certain racial and ethnic groups (see “Background on Minority Health and Health Disparities").

Protein folding in living cells is a complex, error-prone process. Numerous mechanisms are in place to ensure that newly synthesized proteins reach their folded functional form. One of the strategies is the covalent attachment of glycans to Asn residues of nascent polypeptide chains. This process occurs for about 40 % of the total proteins synthesized in mammalian cells and it can be beneficial during maturation by making folding intermediates more soluble. In addition, glycosilation allows the newly synthesized polypeptides to bind to unique lectins present in the endoplasmic reticulum that serve as molecular chaperones. Furthermore, glycoforms have been implicated in driving misfolded glycoproteins to proteasomal degradation. These issues are highly relevant to the so called "conformational diseases". Our goals include the characterization of the molecular determinants that correlate protein stability with the successful or unsuccessful passage of glycoproteins through the endoplasmic reticulum folding quality control mechanism as well as the understanding of how fluctuations in the endoplasmic reticulum Ca²⁺ concentrations affect the subcellular distribution of lectin(s) essential in protein folding quality control.