Abstract
A large number of peripheral membrane proteins transiently interact with lipids through a combination of weak interactions. Among them, electrostatic interactions of clusters of positively charged amino acid residues with negatively charged lipids play an important role. Clusters of charged residues are often found in intrinsically disordered protein regions, which are highly abundant in the vicinity of the membrane forming what has been called the disordered boundary of the cell. Beyond contributing to the stability of the lipid-bound state, the pattern of charged residues may encode specific interactions or properties that form the basis of cell signaling. The element of this code may include, among others, the recognition, clustering, and selective release of phosphatidyl inositides, lipid-mediated protein-protein interactions changing the residence time of the peripheral membrane proteins or driving their approximation to integral membrane proteins. Boundary effects include reduction of dimensionality, protein reorientation, biassing of the conformational ensemble of disordered regions or enhanced 2D diffusion in the peri-membrane region enabled by the fuzzy character of the electrostatic interactions with an extended lipid membrane.
Highlights
The functional integration of the cell with its environment starts in the highly dynamic cell boundary where the interaction of lipids and membrane proteins ensure signal transduction, cell-cell communication, extracellular adhesion, and a myriad of physiological responses of the whole cell initiated at the cell surface.The sharp academic division between soluble and membrane proteins has obscured the importance of peripheral membrane proteins (PMP)
Multiple weak interactions mediate the dynamic interactions between PMPs and the other membrane component and the underlying cytoskeleton
Intrinsically disordered regions (IDR) longer than 30 residues are more abundant in the subset of intrinsic membrane proteins (57%) than in the complete human proteome (34%), suggesting that around 45% of intrinsically disordered regions (IDR) belong to proteins with transmembrane regions
Summary
The functional integration of the cell with its environment starts in the highly dynamic cell boundary where the interaction of lipids and membrane proteins ensure signal transduction, cell-cell communication, extracellular adhesion, and a myriad of physiological responses of the whole cell initiated at the cell surface. While integral membrane proteins are permanently associated to membranes, PMPs interact reversibly with a single membrane leaflet or with the cytoplasmic domains of integral membrane proteins. These transient interactions enable the distribution of PMPs among alternative subcellular compartments, or membrane subdomains, facilitate fast lateral diffusion on the membrane surface, and play a key role in cell signalling. The importance of intrinsic disorder in membrane cell signaling has been recently reviewed [4] This perspective paper is focused on PMPs and is inspired in recent findings on clustering and reversible versus irreversible membrane anchoring by the non-receptor tyrosine kinase Src and the role played by a cluster of basic residues. Clusters of basic residues are common in the intrinsically disordered juxtamembrane region of integral membrane proteins and adjacent to lipid modification sites of other PMP, such as members of the RAS family of GTPases
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