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

TY - JOUR

T1 - Structural basis for a human glycosylation disorder caused by mutation of the COG4 gene

AU - Richardson, Brian C

AU - Smith, Richard D

AU - Ungar, Daniel

AU - Nakamura, Ayumi

AU - Jeffrey, Philip D

AU - Lupashin, Vladimir V

AU - Hughson, Frederick M

PY - 2009/8/11

Y1 - 2009/8/11

N2 - 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.

AB - 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.

KW - Crystallography, X-Ray

KW - DNA Mutational Analysis

KW - Gene Silencing

KW - Glycosylation

KW - Hela Cells

KW - Humans

KW - Membrane Transport Proteins

KW - Mutation

KW - Protein Structure, Secondary

KW - Protein Subunits

KW - Saccharomyces cerevisiae

KW - Saccharomyces cerevisiae Proteins

KW - Structural Homology, Protein

UR - http://www.scopus.com/inward/record.url?scp=69449100200&partnerID=8YFLogxK

U2 - 10.1073/pnas.0901966106

DO - 10.1073/pnas.0901966106

M3 - Article

C2 - 19651599

SN - 0027-8424

VL - 106

SP - 13329

EP - 13334

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

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

IS - 32

ER -