Farooq Amjad
Department of Biochemistry & Molecular Biology, Leonard Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Exp Biol Med (Maywood). 2015 Mar;240(3):361-74. doi: 10.1177/1535370214561586. Epub 2015 Feb 7.
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.
近期关于含WW结构域氧化还原酶（WWOX）肿瘤抑制因子的研究，开始为其WW结构域以及相邻催化结构域的分子作用机制带来新的认识。本文讨论了WW1结构域与各种生理配体结合能力的结构基础，以及在WWOX的WW1-WW2串联模块中孤儿WW2串联伙伴如何协同其配体结合。值得注意的是，WW1-WW2串联模块内的WW结构域在物理上相互关联，从而相对于彼此采用固定的空间取向。通过这种方式，WW2结构域与WW1的结合阻碍了配体与后者的结合。因此，配体与WW1结构域的结合不仅导致WW2盖子的位移，还破坏了配体结合构象中WW结构域的固定取向。同样重要的是，基于结构的功能方法表明，WWOX的催化结构域可能作为一种视网膜氧化还原酶，催化全反式视黄醛的可逆氧化和还原。总体而言，本综述提供了对一种关键信号蛋白功能多样性的结构见解，对其生物学具有重要意义。
