Structure analysis between the SWAP-70 RHO-GEF and the newly described PLD2-GEF

摘要

Small GTPases like Rac2 are crucial regulators of many cell functions central to life itself. Our laboratory has recently found that phospholipase D2 (PLD2) can act as a guanine nucleotide exchange factor (GEF) for Rac2. PLD2 has a Pleckstrin Homology (PH) domain but does not bear a Dbl homology (DH) or DOCK homology region (DHR) domain. It has, however, a Phox (PX) domain upstream of its PH domain. To better understand the novel finding of PLD2 as an enhancer of GDP/GTP exchange, we modeled the N-terminal portion of PLD2 (as the crystal structure of this protein has not as of yet been resolved), and studied the correlation with two known GEFs, SWAP-70 and the Leukemic Associated RhoGEF (LARG). Structural similarities between PLD2’s PH and SWAP-70s or LARG’s PH domain are very extensive, while similarities between PLD2’s PX and SWAP-70s or LARG’s DH domains are less evident. This indicates that PLD functions as a GEF utilizing its PH domain and part of its PX domain and possibly other regions. All this makes PLD unique, and an entirely new class of GEF. By bearing two enzymatic activities (break down of PC and GDP/GTP exchange), it is realistic to assume that PLD is an important signaling node for several intracellular pathways. Future experiments will ascertain how the newly described PLD2’s GEF is regulated in the context of cell activation.