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PDBsum entry 3hr0
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Transport protein
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PDB id
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3hr0
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References listed in PDB file
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Key reference
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Title
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Structural basis for a human glycosylation disorder caused by mutation of the cog4 gene.
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Authors
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B.C.Richardson,
R.D.Smith,
D.Ungar,
A.Nakamura,
P.D.Jeffrey,
V.V.Lupashin,
F.M.Hughson.
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Ref.
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Proc Natl Acad Sci U S A, 2009,
106,
13329-13334.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 1.
X-ray crystal structure of Cog4-(525–785). (A) H. sapiens
Cog4, including residues 536–785. (B) Ionic interaction
network centered around Arg 729.
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Figure 4.
Structural alignment of Cog4-(525–785) to known COG,
exocyst and Dsl1p subunits. (A) Shown are S. cerevisiae Tip20p
(PDB ID 3FHN, residues 4–701 out of 701) (20), Cog2p (2JQQ,
residues 109–262 out of 262) (14), Sec6p (2FJI, residues
411–805 out of 805) (18), Drosophila melanogaster Sec15 (2A2F,
residues 382–699 out of 766) (19), S. cerevisiae Exo84p (2D2S,
residues 525–753 out of 753) (15), and S. cerevisiae Exo70p
(2PFV, residues 67–623 out of 623) (15–17). Pairwise
alignment was performed with the program DaliLite (47) to match
each of the other structures to Cog4-(525–785). The DaliLite Z
scores for the alignments shown were 12.3 (Cog4-Tip20p), 3.8
(Cog4-Cog2p), 13.1 (Cog4-Sec6p), 10.1 (Cog4-Sec15), 6.2
(Cog4-Exo84p), and 8.0 (Cog4-Exo70p). (B) Cog4- (525–785)
superimposed on proteins containing similar domains C, D, and E.
(C) Stereoview of E domains, aligned using DaliLite and with the
N terminus of each domain indicated by a red sphere. Included,
in addition to the structures cited above, are the E domains of
the cargo-binding domain of S. cerevisiae Myo2p (2F6H) (33) and
the Dsl1p complex subunit Dsl1p (Y. Ren, P.D.J., and F.M.H.,
personal communication). No significant alignment was
discernable for domain E of Tip20p.
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