Deciphering the Molecular Mechanism of an Enzymatic Machinery for Glycogen Biosynthesis: DeciphGYG

Programme(s): H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
Topic(s): MSCA-IF-2020 - Individual Fellowships
Call for proposal: H2020-MSCA-IF-2020
Funding Scheme: MSCA-IF-EF-ST - Standard EF
Grant agreement ID: 101025071

Objective
The biosynthesis of glycogen - glycogenesis - represents a key glucose (and hence energy) storage process across a wide range of organisms. Human glycogenin 1 (hGYG1) is one of the two primary enzymes that initiates the biosynthesis of glycogen, our energy reservoir. It polymerizes a maltosaccharide chain covalently attached to an enzyme residue, Y195, via a stepwise glycosylation reaction. In the reaction cycle, a dynamic conformational switch between ground and active states induced by one of the enzyme substrates, the sugar donor UDP-glucose, was predicted by structural studies, including a stretch of a critical loop containing Y195, the acceptor arm, and a major movement of a 32-residue lid covering the active site. The T83M mutation, which causes glycogen storage disease (GSD) type XV, makes the enzyme catalytically inactive. The scientific aim of DeciphGYG is to design a new protocol combining a series of both computational techniques (MD, QM/MM MetaD, HREX and BE-MetaD) and experimental results (NMR and crystallography) to unveil the mechanisms of glycogen biosynthesis, including both the glycosylation reaction as well as its coupling with the conformational changes induced by binding of the UDP-glucose donor and acceptor substrates. The experienced researcher (ER), Qinghua Liao will carry out the project in the University of Barcelona under the supervision of Prof. Carme Rovira, who has extensive experience in computational modeling of carbohydrate-active enzymes. Our goal will be shaping the understanding of hGYG1 action fully on glycogen biosynthesis, facilitating drug design against GSD type XV. Moreover, the new protocol will be transferable to other enzymes of interest in glycobiology. Altogether, the DeciphGYG project will allow the ER with a highly competitive multidisciplinary profile by complementing his previous acquired skills, placing him at a strong position to start his career as an independent and innovative principal investigator.