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

Brian C Richardson, Richard D Smith, Daniel Ungar, Ayumi Nakamura, Philip D Jeffrey, Vladimir V Lupashin, Frederick M Hughson

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)13329-13334
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number32
Publication statusPublished - 11 Aug 2009


  • 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

Cite this