TY - JOUR
T1 - Structural insights into the functional versatility of WW domain-containing oxidoreductase tumor suppressor
AU - Farooq, Amjad
N1 - Funding Information:
I am grateful to Brett Schuchardt for collecting some of the preliminary data discussed here and for many thoughtful discussions. This work was supported by the National Institutes of Health Grant R01-GM083897 and funds from the Sylvester Comprehensive Cancer Center.
Publisher Copyright:
© 2015 by the Society for Experimental Biology and Medicine
PY - 2015/3/25
Y1 - 2015/3/25
N2 - Recent work on WW domain-containing oxidoreductase (WWOX) tumor suppressor is beginning to shed new light on both the molecular mechanism of action of its WW domains as well as the contiguous catalytic domain. Herein, the structural basis underlying the ability of WW1 domain to bind to various physiological ligands and how the orphan WW2 tandem partner synergizes its ligand binding in the context of WW1–WW2 tandem module of WWOX is discussed. Notably, the WW domains within the WW1–WW2 tandem module physically associate so as to adopt a fixed spatial orientation relative to each other. In this manner, the association of WW2 domain with WW1 hinders ligand binding to the latter. Consequently, ligand binding to WW1 domain not only results in the displacement of WW2 lid but also disrupts the fixed orientation of WW domains in the liganded conformation. Equally importantly, structure-guided functional approach suggests that the catalytic domain of WWOX likely serves as a retinal oxidoreductase that catalyzes the reversible oxidation and reduction of all-trans-retinal. Collectively, this review provides structural insights into the functional versatility of a key signaling protein with important implications on its biology.
AB - Recent work on WW domain-containing oxidoreductase (WWOX) tumor suppressor is beginning to shed new light on both the molecular mechanism of action of its WW domains as well as the contiguous catalytic domain. Herein, the structural basis underlying the ability of WW1 domain to bind to various physiological ligands and how the orphan WW2 tandem partner synergizes its ligand binding in the context of WW1–WW2 tandem module of WWOX is discussed. Notably, the WW domains within the WW1–WW2 tandem module physically associate so as to adopt a fixed spatial orientation relative to each other. In this manner, the association of WW2 domain with WW1 hinders ligand binding to the latter. Consequently, ligand binding to WW1 domain not only results in the displacement of WW2 lid but also disrupts the fixed orientation of WW domains in the liganded conformation. Equally importantly, structure-guided functional approach suggests that the catalytic domain of WWOX likely serves as a retinal oxidoreductase that catalyzes the reversible oxidation and reduction of all-trans-retinal. Collectively, this review provides structural insights into the functional versatility of a key signaling protein with important implications on its biology.
KW - WW–ligand interactions
KW - allosteric communication
KW - retinal oxidoreductase
KW - retinoid metabolism
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U2 - 10.1177/1535370214561586
DO - 10.1177/1535370214561586
M3 - Article
C2 - 25662954
AN - SCOPUS:84925294688
VL - 240
SP - 361
EP - 374
JO - Experimental Biology and Medicine
JF - Experimental Biology and Medicine
SN - 0037-9727
IS - 3
ER -