Advanced Concepts and Perspectives of Membrane Physics

Abstract

Highly effective pathways of transmembrane signal transmission are realized by functional membrane domain formation through logistically controlled recruitment of functional proteins to specific sites on cytoplasmic membrane leaflets. Sites of assembly are selected by priming membranes through master switches generating local swarms of super affinity lipid anchors, such as PI(3,4,5)P3 and diacylglycerol (DAG).

Formation and activation of functional domains are regulated by agonistically or antagonistically cooperating molecular switches. We consider here the agonistic Rab4/Rab 5 tandem, serving the rapid receptor recycling, and the antagonistic pair of GTPases Rac-1 and Rho A, controlling the state of the actin cortex. To avoid over-excitations of cells (implying the danger of tumorigenesis), the omnipresent phosphoinositide anchors are protected by layers of the polybasic protein MACKS recruited by electrostatic-hydrophobic forces.

The universality of cell control systems is exemplified by the observation that extrinsic forces and hormones can trigger the generation of very similar types of transmembrane signal transmission centers assembled around receptor tyrosine kinases (RTK). These signal amplifying domains can regulate cellular membrane processes simultaneously through fast biochemical signals, eliciting the rapid structural change of the composite cell envelope, and slow, genetically controlled processes for adapting the mechanical impedances of cells and tissues.

Membrane-based reactions can be controlled via the access of reaction spaces by constituents or enzymes. They can be regulated over large distances by contacting distant membranes through synaptic contacts (such as endoplasmic and of immunological synapses).

Hopefully, insights in the analogy of technical and biological control mechanism may teach us how to generate new self-healing composite materials in logistic ways.

Appendix: Affinity Term Scheme of Bistable Molecular GTPase Switches

GTPases (such as Rac, Rho, and Cdc42) can switch between an inactive state S (with GDP bound) and an active state S* (with GTP bound). In resting cells, the GTPases form inactive complexes with “guanine dissociation inhibitor” GDI or are switched off by internal complex formation (as shown in Fig. 4b for PI-3K). The S→S* transition is induced by uncoupling of the GDI by binding of the GDP→GTP exchange proteins (called guanine nucleotide exchange factors: GEF). As shown in the left image of Fig. 10, the GTPase is generally activated by exchange of GTP for GDP, a process mediated by a GDP→GTP exchange factor (GEF).

Fig. 10

Term scheme of activation and deactivation of the molecular switches of the superfamily family of Ras GTPase, such as Rac-1 and RhoA. (a) Mechanism of activation of the switches by the guanine exchange protein (left) and deactivation by the GTP hydrolyzing protein GAP. Please note that GAP accelerates the turnover of the switches since the (activated) GTP-binding state exhibits a very long lifetime of the order of minutes. Please note that frequently the GDP binding GTPases are stabilized by inhibitors such as GDI. (b) Right top image: Membrane recruitment and activation of a GTPase by the guanine exchange protein GEF mediated by electrostatic-hydrophobic forces. Bottom: the excited GTPase activates and binds an adaptor protein which is also recruited to the membrane by electrostatic-hydrophobic forces. It can attract one or several activators of control processes

GTPases can be recruited to the membrane in two ways. After (or together with) the GTP binding they undergo a conformational change resulting in the exposure of a polybasic peptide sequence and a fatty acid chain. In the case of logistically controlled formation of functional membrane domains, the first step consists in the membrane anchoring of the GEFs; for instance after the generation of high-affinity PI(3,4,5)P3 anchors as shown in the right image.

A second important regulation mechanism is the following. The intrinsic GTP hydrolysis activity of GTPase is very weak resulting in a long lifetime of the activated switches. In order to accelerate this low rate of hydrolysis (which is about 0.01 min⁻¹), another regulatory protein has to come into play, namely, the “GTPase activating proteins” (GAP) (Fig. 10, left). They stimulate the Rho-GTPases to hydrolyze the GTP, thus deactivating the molecular switches rapidly. Taken together, GEF and GAP form a functional tandem that controls the rhythm of the transmembrane signal transmission processes.