 |
PDBsum entry 1r6h
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural insights into molecular function of the metastasis-Associated phosphatase prl-3.
|
|
|
Authors
|
|
G.Kozlov,
J.Cheng,
E.Ziomek,
D.Banville,
K.Gehring,
I.Ekiel.
|
|
|
Ref.
|
|
J Biol Chem, 2004,
279,
11882-11889.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Phosphatases and kinases are the cellular signal transduction enzymes that
control protein phosphorylation. PRL phosphatases constitute a novel class of
small (20 kDa), prenylated phosphatases with oncogenic activity. In particular,
PRL-3 is consistently overexpressed in liver metastasis in colorectal cancer
cells and represents a new therapeutic target. Here, we present the solution
structure of PRL-3, the first structure of a PRL phosphatase. The structure
places PRL phosphatases in the class of dual specificity phosphatases with
closest structural homology to the VHR phosphatase. The structure, coupled with
kinetic studies of site-directed mutants, identifies functionally important
residues and reveals unique features, differentiating PRLs from other
phosphatases. These differences include an unusually hydrophobic active site
without the catalytically important serine/threonine found in most other
phosphatases. The position of the general acid loop indicates the presence of
conformational change upon catalysis. The studies also identify a potential
regulatory role of Cys(49) that forms an intramolecular disulfide bond with the
catalytic Cys(104) even under mildly reducing conditions. Molecular modeling of
the highly homologous PRL-1 and PRL-2 phosphatases revealed unique surface
elements that are potentially important for specificity.
|
|
|
|
|
|
|
|
Figure 1.
FIG. 1. Structure of PRL-3. A, stereo view of the backbone
superposition of the 20 lowest energy structures for residues
Ala^8-Gln156. The unstructured N and C termini are not shown. B,
ribbon representation of the average PRL-3 structure generated
with MOLSCRIPT (41) and Raster3D (42). The secondary structure
elements and N and C termini are labeled.
|
|
Figure 2.
FIG. 2. PRL phosphatases are highly homologous within their
family but show low sequence similarity to the catalytic domains
of other dual specificity phosphatases. The aligned phosphatases
include human PRL-3 (gi:14589856), PRL-1 (gi:4506283), PRL-2
(gi:4506285), Drosophila PRL-1 (gi:3135665), worm PaRaLysed_cae
(gi:17569857), human VHR (gi:181840), CDC14 (gi:34811075), PTEN
(gi:1916328), and KAP (gi:443669). The secondary structural
elements refer to PRL-3. The catalytic residues are shown in
bold type.
|
|
|
|
|
|
The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2004,
279,
11882-11889)
copyright 2004.
|
|
|
|
|
|
|
