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Structural basis for a human glycosylation disorder caused by mutation of the COG4 gene.

The proper glycosylation of proteins trafficking through the Golgi apparatus depends upon the conserved oligomeric Golgi (COG) complex. Defects in COG can cause fatal congenital disorders of glycosylation (CDGs) in humans. The recent discovery of a form of CDG, caused in part by a COG4 missense mutation changing Arg 729 to Trp, prompted us to determine the 1.9 A crystal structure of a Cog4 C-terminal fragment. Arg 729 is found to occupy a key position at the center of a salt bridge network, thereby stabilizing Cog4's small C-terminal domain. Studies in HeLa cells reveal that this C-terminal domain, while not needed for the incorporation of Cog4 into COG complexes, is essential for the proper glycosylation of cell surface proteins. We also find that Cog4 bears a strong structural resemblance to exocyst and Dsl1p complex subunits. These complexes and others have been proposed to function by mediating the initial tethering between transport vesicles and their membrane targets; the emerging structural similarities provide strong evidence of a common evolutionary origin and may reflect shared mechanisms of action.

Pubmed ID: 19651599

Authors

  • Richardson BC
  • Smith RD
  • Ungar D
  • Nakamura A
  • Jeffrey PD
  • Lupashin VV
  • Hughson FM

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

August 11, 2009

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM071574
  • Agency: NIGMS NIH HHS, Id: GM083144
  • Agency: NIBIB NIH HHS, Id: P30 EB009998
  • Agency: NIGMS NIH HHS, Id: R01 GM083144
  • Agency: NIGMS NIH HHS, Id: R01 GM083144-01A1

Mesh Terms

  • Crystallography, X-Ray
  • DNA Mutational Analysis
  • Gene Silencing
  • Glycosylation
  • HeLa Cells
  • Humans
  • Membrane Transport Proteins
  • Mutation
  • Protein Structure, Secondary
  • Protein Subunits
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Structural Homology, Protein