Abstract
WASp-interacting protein (WIP), a regulator of actin cytoskeleton assembly and remodeling, is a cellular multi-tasker and a key member of a network of protein–protein interactions, with significant impact on health and disease. Here, we attempt to complement the well-established understanding of WIP function from cell biology studies, summarized in several reviews, with a structural description of WIP interactions, highlighting works that present a molecular view of WIP’s protein–protein interactions. This provides a deeper understanding of the mechanisms by which WIP mediates its biological functions. The fully disordered WIP also serves as an intriguing example of how intrinsically disordered proteins (IDPs) exert their function. WIP consists of consecutive small functional domains and motifs that interact with a host of cellular partners, with a striking preponderance of proline-rich motif capable of interactions with several well-recognized binding partners; indeed, over 30% of the WIP primary structure are proline residues. We focus on the binding motifs and binding interfaces of three important WIP segments, the actin-binding N-terminal domain, the central domain that binds SH3 domains of various interaction partners, and the WASp-binding C-terminal domain. Beyond the obvious importance of a more fundamental understanding of the biology of this central cellular player, this approach carries an immediate and highly beneficial effect on drug-design efforts targeting WIP and its binding partners. These factors make the value of such structural studies, challenging as they are, readily apparent.
Highlights
Modern biochemical research emphasizes the importance of complementing the biological and functional description of cellular events with a structural understanding of these on the molecular level. Such a combined structure-function view of biology—and the biomacromolecules that power it—has been repeatedly established as a prerequisite for studying biological pathways, analyzing signaling and regulation cascades, efficient drug design and optimization, and other investigation avenues that focus the majority of research efforts today. This state of affairs has motivated the development and advancement of experimental techniques capable of addressing this need, the main ones being X-ray crystallography, nuclear magnetic resonance (NMR), cryo-electron microscopy, mass-spectrometry (MS), fluorescence-based spectroscopy, and a variety of scattering methods
WASp-interacting protein (WIP) regulates the activation of both WASp, found in hematopoietic cells, and its ubiquitously expressed homolog N-WASp, nucleation-promoting factors (NPFs) that stimulate the molecular apparatus actin-related protein 2/3 (Arp2/3) complex to assemble filamentous actin
Its first discovered role was in mediating the immune response, much research since has established important functions in cytoskeletal changes via its interaction with G- and F-actin under different conditions, regulation via interaction with several adaptor proteins, and maturation and synaptic activity of neuronal cells
Summary
Modern biochemical research emphasizes the importance of complementing the biological and functional description of cellular events with a structural understanding of these on the molecular level Such a combined structure-function view of biology—and the biomacromolecules that power it—has been repeatedly established as a prerequisite for studying biological pathways, analyzing signaling and regulation cascades, efficient drug design and optimization, and other investigation avenues that focus the majority of research efforts today. This state of affairs has motivated the development and advancement of experimental techniques capable of addressing this need, the main ones being X-ray crystallography, nuclear magnetic resonance (NMR), cryo-electron microscopy (cryo-EM), mass-spectrometry (MS), fluorescence-based spectroscopy, and a variety of scattering methods. We will attempt to outline prospects for future structural study of this important system
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
