 |
PDBsum entry 2qt5
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Peptide binding protein
|
PDB id
|
|
|
|
2qt5
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Supramodular nature of grip1 revealed by the structure of its pdz12 tandem in complex with the carboxyl tail of fras1.
|
|
|
Authors
|
|
J.Long,
Z.Wei,
W.Feng,
C.Yu,
Y.X.Zhao,
M.Zhang.
|
|
|
Ref.
|
|
J Mol Biol, 2008,
375,
1457-1468.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The scaffold protein GRIP1 (glutamate receptor interacting protein 1) binds to
and regulates both the trafficking and membrane organization of a large number
of transmembrane proteins. Mutation of GRIP1 in mice displays essentially the
same phenotype of the mutations of Fras1 or Frem2, which are the animal models
of the human genetic disorder Fraser syndrome. However, the molecular basis
governing the interaction between GRIP1 and Fras1/Frem2 is unknown. Here, we
show that interaction between Fras1 and GRIP1 requires the first two PDZ domains
(PDZ1 and PDZ2) to be connected in tandem, as the folding of PDZ1 strictly
depends on the covalent attachment of PDZ2. The crystal structure of GRIP1 PDZ12
in complex with the Fras1 C-terminal peptide reveals that the PDZ12 tandem forms
a supramodule in which only the peptide-binding groove of PDZ1 is bound with the
Fras1 peptide. The GRIP1 PDZ12/Fras1 peptide complex not only provides a
mechanistic explanation of the link between GRIP1 and the Fraser syndrome but
may also serve as a foundation for searching for potential mutations in GRIP1
that could lead to the Fraser syndrome.
|
|
|
|
|
|
|
|
Figure 3.
Fig. 3. The overall structure of the GRIP1 PDZ12 tandem in
complex with the Fras1 peptide. (a) Ribbon diagram
representation showing the stereoview of the backbone structure
of the GRIP1 PDZ12 tandem in complex with the Fras1 peptide.
PDZ1 (residues 48–135), PDZ2 (residues 145–240), and
Loop[1–2] (residues 136–144) are colored blue, green, and
yellow, respectively. (b) A semitransparent surface
representation of the PDZ12 tandem showing that the two PDZ
domains interact with each other in a front-to-back fashion to
form a structurally intact supramodule. The figure also
illustrates that the hypothetical target-binding groove of PDZ2
(highlighted with a red oval) is occupied by residues from the
βA-, αA-, and the αA/βD-loop regions of PDZ1 and, therefore,
inaccessible to peptide ligands. (c) Overlay plot of the
backbone structures of PDZ1 and PDZ2 showing the similarity of
their overall conformation. The different conformation of the
βB/βC-loop between the two PDZ domains is highlighted by a
purple oval.
|
|
Figure 5.
Fig. 5. Multiple sequence alignment of the PDZ12 tandem of
GRIP from different species. The protein sequences were from
rat, human, zebrafish, and fruit fly. In this diagram, residues
that are identical and similar are shown in red and yellow
boxes, respectively. The secondary structural elements are
indicated above the alignment and are colored blue (for PDZ1)
and green (for PDZ2). The amino acid residues in PDZ1 that are
directly involved in the Fras1 peptide binding are highlighted
with triangles, and the residues labeled with asterisks are
critical for the interdomain interaction between PDZ1 and PDZ2.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2008,
375,
1457-1468)
copyright 2008.
|
|
|
|
|
|
|
