# Ras Multimers on the Membrane: Many Ways for a Heart-to-Heart Conversation
## 7 Concluding Remarks  
Since our last review on this topic [32], significant advances have been made in our understanding of Ras dimers. Ras dimer formation has now been recognized as a key step in the activation of Raf [65; 81; 98; 219] and potentially other effectors [33]. In the pursuit of a better understanding of Ras dimer biology, the field has also gained rich, new insights into how Ras interacts with the membrane and its signaling partners. These new insights have contributed to the reviving enthusiasm toward drugging mutant Ras. Strategies that target the Ras dimer interface have shown their initial promises as novel therapeutics against mutant Ras, adding to the small but growing list of options for tackling this difficult drug target. An important observation from existing work is that Ras can potentially dimerize at a variety of G-domain interfaces. The most notable is the \(\alpha\)4-\(\alpha\)5 dimer interface, which has been repeatedly observed in computational and experimental studies [85; 92; 117; 118]. Also observed experimentally are the \(\alpha\)3-\(\alpha\)4 and \(\beta\)2-\(\beta\)3 interfaces (and the close variations), and their physiological relevance has yet to be further studied. In addition to dimerization using symmetric interfaces, asymmetric dimers using an \(\alpha\)-\(\beta\) interface is also permitted and may facilitate transition from dimers to nanoclusters [71]. Heterotypic dimers between Ras-GDP and Ras-GTP are also likely and could account for the tumor suppressor effect of WT Ras [65; 91]. While dimerization is common in signaling proteins, such a degree of variability in the dimerization interface could make Ras a unique case. The possibility of using multiple dimerization interfaces implies that Ras dimerization is not a simple 'on-off' switch. Instead, by adjusting the ratios of the different dimer variants--including nanoclusters--the population and lifetime of the 'competent' dimers can be finetuned. The means to achieve this tuning can be manifold: local concentration of Ras, the surrounding lipid composition, the local membrane topography, and the presence of binding partners, among others. Biological membranes feature numerous types of nanoscale to microscale domains, each of which comprise a unique molecular composition, structure, and accessibility, and are thus ideal platforms to build a signaling module like one around Ras. Each type of membrane domain will therefore be associated with a unique 'dimer' profile, which in turn correspond to a specific subset of biological processes (Figure 8). Studies on Ras dimers, nanoclusters in cells as well as in reconstituted membrane systems have gained much insight into Ras-membrane interactions. Defining the specific types of Ras-associated membrane nanodomains and how they regulate Ras dimerization will be a critical next step toward understanding how Ras operates on the cell membrane. While current work is mostly at a proof-of-concept stage, development of agents that manipulate Ras dimers as mutant Ras-targeted therapeutics is an exciting prospect for the field. Initial work assuming a single, well-defined dimer interface aimed to develop agents that block the dimer interface. At least one of such agents, the NS1 monopody, has demonstrated its utility in model systems [98; 109]. The realization that Ras may use multiple dimer interfaces presents another opportunity for manipulating Ras activity--inducing the unproductive dimers, as demonstrated using the small molecule BI-2852 [71; 220; 221]. Aside from potential use as therapeutics, many of these agents will be useful tool molecules for Ras dimer research. In the past several there has been great success in combining experimental investigations with computer modeling in tackling the mysteries of Ras dimers. Results from multiple disciplines are reaching a critical mass and already starting to converge on some key points. There is a good reason to believe that a more exciting era for Ras biology is yet to come. Conceptualization, E.S.O., A.M.K. and X.N.