Higher-order assemblies in a new paradigm of signal transduction

Abstract

Recent studies have revealed that multiple intracellular signaling proteins may assemble into structured, yet sometimes infinite, higher-order signaling machines for transmission of receptor activation information to cellular responses. These studies advance our understanding of cell signaling and implicate new molecular mechanisms in proximity-driven enzyme activation, threshold behavior, signal amplification, reduction of biological noise, and temporal and spatial control of signal transduction.

Figure 1. Classical and Higher-Order Assembly Modes of Signal Transduction

(A) A classical view of receptor signal transduction involving successive steps of activation of intracellular signaling proteins (denoted S₁ to S₃ as examples). Asterisks are used to indicate activated forms of receptors and signaling proteins. (B) A view of receptor signal transduction involving formation of higher-order oligomeric signalosomes between receptors and signaling proteins, with implications in proximity-induced enzyme activation, threshold behavior, signal amplification, and spatial regulation. Two potential amplification mechanisms are illustrated respectively by incorporation of unliganded receptors and recruitment of overstoichiometric number of signaling proteins (dotted lines) into the signalosome. It should be noted that, although the extracellular domains of many such receptors form defined oligomers, extensive evidence suggests higher-order lateral clustering of full-length receptors. (C) Crystal structure of a higher-order signalosome assembly, showing the formation using helical symmetry of a 14 subunit complex containing the DD of six MyD88 (an adaptor protein, in cyan), four IRAK4 (a kinase, in yellow), and four IRAK2 (a kinase, in red) molecules (Lin et al., 2010). Similar helical symmetries may mediate the formation of infinite filamentous structures. (D) Schematic diagram of an amyloid assembly in signaling (Li et al., 2012a). Arrows indicate βstrands. (E) A proposed two-dimensional lattice structure of TRAF6 formed by alternating dimerization and trimerization (Yin et al., 2009). (F) Simulated response curves as a function of dose of stimulation in arbitrary units (a.u.) for differentially cooperative processes. N: Hill coefficients. The off-state and on-state locations of highly cooperative processes are indicated. (G) Simulated response curves as a function of time in arbitrary units (a.u.). N: Hill coefficients. A delay in response for a highly cooperative process may act as a noise filter in response.