Background: Activin receptor-like kinase 1 (ALK1) is an important regulator of normal blood vessel formation and pathological tumor angiogenesis. Results: Crystal structure of ALK1-BMP9-ACTRIIB signaling complex and kinetic and thermodynamic properties of receptorligand interactions are described. Conclusions: ALK1 achieves high specificity for BMP9/10 through unusual receptor positioning and unique receptor-ligand interface. Significance: Structural and mechanistic insights into ALK1 signaling provide a framework for novel anti-angiogenic therapies.

Mosquitoes transmit pathogens that kill >700,000 people annually. These insects use body heat to locate and feed on warm-blooded hosts, but the molecular basis of such behavior is unknown. Here, we identify ionotropic receptor IR21a, a receptor conserved throughout insects, as a key mediator of heat seeking in the malaria vector Anopheles gambiae. Although Ir21a mediates heat avoidance in Drosophila, we find it drives heat seeking and heat-stimulated blood feeding in Anopheles. At a cellular level, Ir21a is essential for the detection of cooling, suggesting that during evolution mosquito heat seeking relied on cooling-mediated repulsion. Our data indicate that the evolution of blood feeding in Anopheles involves repurposing an ancestral thermoreceptor from non–blood-feeding Diptera.

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Mosquito-borne diseases sicken >500,000,000 people annually, killing >500,0001. Mosquito host-seeking is guided by multiple host-associated cues, which combine to drive blood feeding in a manner that remains poorly understood2,3. While heat is a powerful mosquito attractant, recent studies indicate that disruption of heat seeking has little impact on host detection by the malaria vector Anopheles gambiae4, suggesting other cues act alongside heat in the complex sensory environment of a human host. Here we show mosquitoes require Ir93a (an Ionotropic Receptor5) to maintain attraction to a human host and feed on warmed blood. Using Ir93a, we uncover the previously uncharacterized mosquito hygrosensory system, and show Ir93a is required for humidity detection by humidity sensors (hygrosensors) as well as temperature detection by thermosensors, and for attraction to each stimulus. These findings indicate that hygrosensation and thermosensation function in parallel, driving host proximity detection in response to the overlapping heat and humidity gradients humans produce6,7. These host cue sensors appear to have arisen by co-opting existing sensors of physical cues rather than de novo, as Ir93a-dependent thermo- and hygro-sensors support physiological homeostasis in non-blood-feeding insects8-11. While Ir93a is conserved among arthropods, reliance on heat and humidity evolved independently in multiple blood-feeding lineages, suggesting multiple, vector-specific implementations of this common host-seeking strategy.

A temperature-sensitive receptor prevents mosquitoes from being attracted to targets that are hotter than a potential host.