title: 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.
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5;
authors: Elton
authors: E
authors: Zeqiraj
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5;
authors: Xiaojing
authors: X
authors: Tang
authors: Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors: Roger W
authors: RW
authors: Hunter
authors: Institute for Research in Biomedicine, 08028 Barcelona, Spain;
authors: Mar
authors: M
authors: García-Rocha
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5;
authors: Andrew
authors: A
authors: Judd
authors: Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors: Maria
authors: M
authors: Deak
authors: Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors: Alexander
authors: A
authors: von Wilamowitz-Moellendorff
authors: Department of Chemistry and Chemical Biology, Cornell University, Argonne, IL 60439;
authors: Igor
authors: I
authors: Kurinov
authors: Institute for Research in Biomedicine, 08028 Barcelona, Spain;Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain;
authors: Joan J
authors: JJ
authors: Guinovart
authors: Institute for Research in Immunology and Cancer andDepartment of Medicine, University of Montreal, Montreal, QC, Canada H3C 3J7; and sicheri@lunenfeld.ca md.tyers@umontreal.ca kei.sakamoto@rd.nestle.com.
authors: Mike
authors: M
authors: Tyers
authors: Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom; sicheri@lunenfeld.ca md.tyers@umontreal.ca kei.sakamoto@rd.nestle.com.
authors: Kei
authors: K
authors: Sakamoto
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5;Department of Biochemistry andDepartment of Molecular Genetics, University of Toronto, Toronto, Canada M5S 1A8 sicheri@lunenfeld.ca md.tyers@umontreal.ca kei.sakamoto@rd.nestle.com.
authors: Frank
authors: F
authors: Sicheri
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002474:Cell-Free System; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D005964:Glucosyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D006006:Glycogen Synthase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship
chemical_list: D029742:Caenorhabditis elegans Proteins; D006023:Glycoproteins; C051887:glycogenin; D006003:Glycogen; D005964:Glucosyltransferases; D006006:Glycogen Synthase
keywords: energy metabolism; glucose metabolism; glycogenesis; starch