Around 20% of eukaryotic genes code for secreted glycoproteins, which carry out a number of important functions in cellular metabolisms, immune response and cell signalling. A sophisticated quality control system in the Endosplamic Reticulum (ERQC) of the eukaryotic cell checks and aids proper folding of glycoproteins en route to secretion, making sure that misfolded glycoproteins are correctly folded before they progress to the Golgi and the appropriate cellular or extracellular destination. A research team comprising the Institute of Sciences of Food Production Unit of Lecce (Ispa-Cnr) and the Institute of Crystallography of Bari of the Consiglio Nazionale delle Ricerche have determined for the first time the complete crystal structure of one of the main ERQC components, the checkpoint enzyme UDP-Glucose glycoprotein glucosyltranseferase (aka UGGT). The study suggests that UGGT’s ability to detect misfold in substrate glycoproteins of many different sizes and folds depends on its inter-domain conformational flexibility. The publication, in collaboration with Nicole Zitzmann e Pietro Roversi at the Oxford Glycobiology Institute at the Department of Biochemistry, of the University of Oxford (UK) has just appeared in the journal PNAS.
“Modulation of the activity of enzymes such as UGGT – explains Angelo Santino from Ispa-Cnr - offers a potential therapeutic strategy for many congenitals glycoprotein folding disorders, whenever the disease is caused by a mutation that causes the glycoprotein to misfold but does not abrogate its activity (“responsive mutants”). This is the case for example for 70% of the patients affected by Cystic fibrosis, and for a fraction of patients affected by lysosomal storage diseases such as Gaucher disease. ERQC modulation in these cases could rescue secretion of the misfolded and yet active glycoprotein and restore activity, at least partially, alleviating the symptoms.”
“We conducted our experiments on Arabidopsis thaliana plants – explains Lucia Marti from Ispa-Cnr - because there already existed plant lines with a non-functional ERQC genes. This in turn allowed us to study the activity of the ERQC enzymes, observing the plant phenotype, as well as carry out preliminary screening of potential ERQC inhibitors, which - before being assayed in animal models - can be successfully tested in the plant with much lower costs and no ethical limitations.”
Study: 'Interdomain conformational flexibility underpins the activity of Uggt, the eukaryotic glycoprotein secretion checkpoint' Roversi P, Marti L, Caputo AT, Alonzi DS, Hill JC, Dent KC, Kumar A, Levasseur MD, Lia A, Waksman T, Basu S, Soto Albrecht Y, Qian K, McIvor JP, Lipp CB, Siliqi D, Vasiljevi S, Mohammed S, Lukacik P, Walsh MA, Santino A, Zitzmann N. 2017 Aug 8;114(32):8544-8549. doi: 10.1073/pnas.1703682114.
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