Basic Residue Clusters in Intrinsically Disordered Regions of Peripheral Membrane Proteins: Modulating 2D Diffusion on Cell Membranes

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.

Lipid-mediated dimerization of membrane-anchored c-Src is driven by a cluster of lysine residues in the N-terminal SH4 domain

“…Although dimers represent a minor fraction of membrane-anchored c-Src, their much slower release and the possibility for enhanced trans-activation, suggest that they could represent enhanced signaling hot spots. These finding also highlight the important role of lipids in the regulation of a non-receptor protein kinase and suggests an important role of lipids, charged or neutral, in mediating protein-protein interactions through the abundant juxtamembrane charged clusters (18).…”

“…SFK mixed dimers). In the case of c-Src, the strong lipid binding of dimers, together with the intrinsic low membrane affinity of monomers, offer an efficient search mechanism to find the relevant membrane regions where signaling partners are located: weak lipid binding offers an efficient 2D diffusion mechanism, crossing corralling fences, while dimerization, induced by local signals (activated receptors, specific lipids…) can anchor and activate c-Src triggering its downstream signaling (12,13,18).…”

“…In the ensemble of the 58 human receptor tyrosine kinases, the juxtamembrane region protruding into the cytoplasm is enriched in positively charged residues. The initial 20 residues following the transmembrane helix contain 25% of basic residues and only 11% acidic ones (18). A positive cluster, containing lysine and arginine residues ( 51 YA RKR NGQM 59 ) is located in the small cytoplasmic tail extending from the small integral membrane protein SMIM30 encoded by lncRNA LINC0998.…”

Machine learning in computational modelling of membrane protein sequences and structures: From methodologies to applications

“…Membrane proteins, comprised of integral and peripheral membrane proteins, are replete with intrinsic biochemical and biophysical properties that are crucial in manifold biological functions [49] , such as signal transduction [50] and enzymatic activity [51] . Integral membrane (IM) proteins, which comprise a substantial proportion of the membrane proteome, are permanently embedded in lipid bilayers [52] , [53] , [54] , while peripheral membrane (PM) proteins often bind transiently to the surface and are comparatively rare [55] , [56] , [57] . Both types of proteins morphologically interact with plasma lipids in many ways [49] , [58] , [59] .…”