Oligomerization and nanocluster organization render specificity
Tóm tắt
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.
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Tài liệu tham khảo
Ghosh S., 1996, Raf‐1 kinase possesses distinct binding domains for phosphatidylserine and phosphatidic acid. Phosphatidic acid regulates the translocation of Raf‐1 in 12‐O‐tetradecanoylphorbol‐13‐acetate‐stimulated Madin‐Darby canine kidney cells, The Journal of Biological Chemistry, 271, 8472, 10.1074/jbc.271.14.8472
Ghosh S., 1994, The cysteine‐rich region of raf‐1 kinase contains zinc, translocates to liposomes, and is adjacent to a segment that binds GTP‐ras, The Journal of Biological Chemistry, 269, 10000, 10.1016/S0021-9258(17)36981-8
Klammt C., 2012, How membrane structures control T cell signaling, Frontiers in Immunology, 3, 291(9)