Bodily awareness and novel multisensory features

According to the decomposition thesis, perceptual experiences resolve without remainder into their different modality-specific components. Contrary to this view, I argue that certain cases of multisensory integration give rise to experiences representing features of a novel type. Through the coordinated use of bodily awareness—understood here as encompassing both proprioception and kinaesthesis—and the exteroceptive sensory modalities, one becomes perceptually responsive to spatial features whose instances couldn’t be represented by any of the contributing modalities functioning in isolation. I develop an argument for this conclusion focusing on two cases: 3D shape perception in haptic touch and experiencing an object’s egocentric location in crossmodally accessible, environmental space

Structural basis of Smoothened regulation by its extracellular domains

Developmental signals of the Hedgehog (Hh) and Wnt families are transduced across the membrane by Frizzledclass G-protein-coupled receptors (GPCRs) composed of both a heptahelical transmembrane domain (TMD) and an extracellular cysteine-rich domain (CRD). How the large extracellular domains of GPCRs regulate signalling by the TMD is unknown. We present crystal structures of the Hh signal transducer and oncoprotein Smoothened, a GPCR that contains two distinct ligand-binding sites: one in its TMD and one in the CRD. The CRD is stacked a top the TMD, separated by an intervening wedge-like linker domain. Structure-guided mutations show that the interface between the CRD, linker domain and TMD stabilizes the inactive state of Smoothened. Unexpectedly, we find a cholesterol molecule bound to Smoothened in the CRD binding site. Mutations predicted to prevent cholesterol binding impair the ability of Smoothened to transmit native Hh signals. Binding of a clinically used antagonist, vismodegib, to the TMD induces a conformational change that is propagated to the CRD, resulting in loss of cholesterol from the CRD-linker domain-TMD interface. Our results clarify the structural mechanism by which the activity of a GPCR is controlled by ligand-regulated interactions between its extracellular and transmembrane domains