Abstract
INAD assembles key enzymes of the Drosophila compound eye photo-transduction pathway into a supramolecular complex, supporting efficient and fast light signaling. However, the molecular mechanism that governs the interaction between INAD and NORPA (phospholipase Cβ, PLCβ), a key step for the fast kinetics of the light signaling, is not known. Here, we show that the NORPA C-terminal coiled-coil domain and PDZ-binding motif (CC-PBM) synergistically bind to INAD PDZ45 tandem with an unexpected mode and unprecedented high affinity. Guided by the structure of the INAD-NORPA complex, we discover that INADL is probably a mammalian counterpart of INAD. The INADL PDZ89 tandem specifically binds to PLCβ4 with a mode that is strikingly similar to that of the INAD-NORPA complex, as revealed by the structure of the INADL PDZ89-PLCβ4 CC-PBM complex. Therefore, our study suggests that the highly specific PDZ tandem - PLCβ interactions are an evolutionarily conserved mechanism in PLCβ signaling in the animal kingdom.
Highlights
Scaffold proteins can serve as platforms for the assembly of signaling components into macromolecular complexes, targeting them to specific cellular localizations, as well as actively modulating signaling processes (Bhattacharyya et al, 2006; Pawson and Nash, 2003; Zhang and Wang, 2003)
We discover that the INAD PDZ45 supramodule binds to the coiled-coil domain and PDZ-binding motif (CC-PDZ binding motif (PBM)) domain of NORPA with very strong binding affinity
The stringent conformational requirement of both proteins for the tight binding means that the interaction between INAD PDZ45 and the NORPA coiled coil (CC)-PBM is highly specific
Summary
Scaffold proteins can serve as platforms for the assembly of signaling components into macromolecular complexes, targeting them to specific cellular localizations, as well as actively modulating signaling processes (Bhattacharyya et al, 2006; Pawson and Nash, 2003; Zhang and Wang, 2003). The Drosophila compound eye rhodopsin-mediated photo-transduction signaling process is highly elaborate It is one of the best-studied model systems showing how light signals, via INAD scaffold-organized signaling complexes, can be transduced at a very large dynamic range with extremely rapid kinetics and intricate regulatory mechanisms (Huber, 2001; Li and Montell, 2000; Liu et al, 2011; Mishra et al, 2007; Tsunoda et al, 1997; Tsunoda and Zuker, 1999). The striking similarity between the PDZ scaffold and PLCb interactions at the molecular level might point to an evolutionarily conserved molecular adaption in PLCb signaling in the animal kingdom
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