Structural basis for the recruitment of glycogen synthase by glycogenin

Abstract

Glycogen is a primary form of energy storage in eukaryotes that is essential for glucose homeostasis. The glycogen polymer is synthesized from glucose through the cooperative action of glycogen synthase (GS), glycogenin (GN), and glycogen branching enzyme and forms particles that range in size from 10 to 290 nm. GS is regulated by allosteric activation upon glucose-6-phosphate binding and inactivation by phosphorylation on its N-and C-terminal regulatory tails. GS alone is incapable of starting synthesis of a glycogen particle de novo, but instead it extends preexisting chains initiated by glycogenin. The molecular determinants by which GS recognizes self-glucosylated GN, the first step in glycogenesis, are unknown. We describe the crystal structure of Caenorhabditis elegans GS in complex with a minimal GS targeting sequence in GN and show that a 34-residue region of GN binds to a conserved surface on GS that is distinct from previously characterized allosteric and binding surfaces on the enzyme. The interaction identified in the GS-GN costructure is required for GS-GN interaction and for glycogen synthesis in a cell-free system and in intact cells. The interaction of full-length GS-GN proteins is enhanced by an avidity effect imparted by a dimeric state of GN and a tetrameric state of GS. Finally, the structure of the N-and C-terminal regulatory tails of GS provide a basis for understanding phosphoregulation of glycogen synthesis. These results uncover a central molecular mechanism that governs glycogen metabolism.glucose metabolism | energy metabolism | glycogenesis | starch

Redox Switch for the Inhibited State of Yeast Glycogen Synthase Mimics Regulation by Phosphorylation

“…The structure of Ce GS showed that the N-terminal phospho-sites are positioned in such a way that they can interact with the regulatory helix 13 . The phospho-sites, Ser12 and Thr19 are separated from the cis-regulatory helix by only 6–16 Å 13 .…”

“…The structure of Ce GS showed that the N-terminal phospho-sites are positioned in such a way that they can interact with the regulatory helix 13 . The phospho-sites, Ser12 and Thr19 are separated from the cis-regulatory helix by only 6–16 Å 13 . The authors proposed that upon phosphorylation, the N-terminal tail could dissociate itself from its ordered position and engage with the charged arginine residues 13 .…”

“…Crystal structures are available only for two eukaryotic glycogen synthases, Saccharomyces cerevisia e and Caenorhabditis elegans 10, 13 . The crystal structure of the yeast Gsy2 was solved for both the intermediate state and the G-6-P activated state.…”

From structural biology to designing therapy for inborn errors of metabolism

“…Miglustat for the treatment of Gaucher disease (Platt and Jeyakumar 2008)) to reduce the consequence of toxic metabolite accumulation due to defective enzymes (Schiffmann 2015). We anticipate that progress in the structural biology of GYS and GYG (Chaikuad et al 2011; Zeqiraj et al 2014) should pave the next step forward in developing novel inhibitors for these enzymes. This example therefore illustrates the principle of targeting different components of a metabolic pathway for the treatment of a genetic disease.…”

A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase

“…Although the crystal structure has not been published for any mammalian GS, the structures for a bacterial GT5 synthase ( Agrobacterium tumefaciens ) [2] and, more recently, for a yeast synthase ( Saccharomyces cerevisiae ; Gsy2p) [26] and a Caenorhabditis elegans synthase [27] have been solved. Yeast GS is a homo-tetrameric protein in both its basal and active states and eukaryotic GT3 synthases likely have a similar tetrameric arrangement due to their high sequence identity [26].…”