title: Oligomerization and nanocluster organization render specificity.
abstract: Nanoclusters are anchored to membranes, either within them or in the cytoplasm latched onto the cytoskeleton, whose reorganization can regulate their activity. Nanoclusters have been viewed in terms of cooperativity and activation; here we perceive nanocluster organization from a conformational standpoint. This leads us to suggest that while single molecules encode activity, nanoclusters induce specificity, and that this is their main evolutionary aim. Distinct, isoform-specific nanocluster organization can drive the preferred effector (and ligand) interactions and thereby designate signalling pathways. The absence of detailed structural information across the nanocluster, due to size and dynamics, hinders an in-depth grasp of its mechanistic features; however, available data already capture some of the principles and their functional 'raison d'être'. Collectively, clustering lends stability and reduces the likelihood of proteolytic cleavage; it also increases the effective local concentration and enables efficient cooperative activation. However, clustering does not determine the ability of the single molecule to function. Drugs targeting nanoclusters can attenuate activity by hampering cooperativity; however, this may not perturb activation and signalling, which originate from the molecules themselves, and as such, are likely to endure. What then is the major role of nanoclustering? Assuming that single molecules evolved first, with a subsequent increase in cellular complexity and emergence of highly similar isoform variants, evolution faced the threat of signalling promiscuity. We reason that this potential risk was thwarted by oligomerization and clustering; clustering confers higher specificity, and a concomitant extra layer of cellular control. In our Ras example, signalling will be more accurate as a dimer than as a monomer, where its isomer specificity could be compromised.
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, National Cancer Institute, Frederick, MD 21702, U.S.A.; Department of Human Genetics and Molecular Medicine, Sackler Institute of Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Tsai
mesh_terms: D002450:Cell Communication; D002462:Cell Membrane / Q000502:physiology; D003599:Cytoskeleton / Q000502:physiology*; D005786:Gene Expression Regulation; D008055:Lipids / Q000737:chemistry; D021962:Membrane Microdomains
chemical_list: D008055:Lipids
keywords: Ras; allosteric; allostery; co-localization; conformational states; cytoskeleton; microclusters; nanoclusters; oligomerization; scaffolding; signalling; structure