Membrane binding of intrinsically disordered proteins: Critical importance of an appropriate membrane model

Abstract

Intrinsically disordered proteins (IDPs) are proteins that lack a well-defined three-dimensional structure under physiological conditions. In this context, cytoplasmic regions of signaling subunits of immune receptors, including those of ζ and CD3ε signaling subunits (ζcyt and CD3εcyt, respectively) of T cell receptor (TCR), and γ signaling subunit of FcεRI receptor (FcεRIγcyt) represent a novel class of IDPs. 1-3 These regions all have one or more copies of an immunoreceptor tyrosine-based activation motif (ITAM), tyrosine residues of which are phosphorylated upon receptor engagement in an early and obligatory event in the signaling cascade. Considering a crucial role of ζcyt, CD3εcyt and FcεRIγcyt in immune signaling and their close proximity to the cell membrane, the question whether or not membrane binding of these IDPs can promote folding of ζcyt, CD3εcyt and FcεRIγcyt ITAMs and thus lead to inaccessibility of the ITAM tyrosines for phosphorylation is of fundamental importance in our understanding of receptor triggering. However, little is known about lipid-binding activity of the ITAM-containing cytoplasmic domains and the existing data are strikingly contradictory (Fig. 1).1,2,4 Our recent study5 provides, for the first time, molecular explanation of discrepancies in the literature and demonstrates that the use of an inappropriate membrane model can result in misleading conclusions regarding membrane-binding activity of proteins and its physiological relevance. © 2010 Landes Bioscience.