SUMMARY Arc is a cellular immediate early gene (IEG) that functions at excitatory synapses and is required for learning and memory. We report crystal structures of Arc subdomains that form a bi-lobar architecture remarkably similar to the capsid domain of human immunodeficiency virus (HIV) gag protein. Analysis indicates Arc originated from the Ty3/Gypsy retrotransposon family and was “domesticated” in higher vertebrates for synaptic functions. The Arc N-terminal lobe evolved a unique hydrophobic pocket that mediates intermolecular binding with synaptic proteins as resolved in complexes with TARPγ2 (Stargazin) and CaMKII peptides, and is essential for Arc’s synaptic function. A consensus sequence for Arc binding identifies several additional partners that include genes implicated in schizophrenia. Arc N-lobe binding is inhibited by small chemicals suggesting Arc’s synaptic action may be druggable. These studies reveal the remarkable evolutionary origin of Arc and provide a structural basis for understanding Arc’s contribution to neural plasticity and disease.

These results show that all mammalian Hh proteins bind CDO and BOC in the same manner. We also show that interactions between Hh proteins and CDO are weakened at low pH. Formation of Hh-mediated Hh oligomers is thought to be an important feature of normal Hh signaling, but no conserved self-interaction between Hh proteins is apparent from inspection of 14 independent Hh-containing crystal lattices.Hedgehog (Hh) 2 signaling proteins mediate key cell differentiation and tissue patterning events during animal development (1-3). Hh proteins generate tissue pattern, and fit the classical definition of a morphogen, by forming concentration gradients emanating from sites of secretion and eliciting different cell fate responses at different concentrations (3, 4). Three Hh homologs are present in mammals: Sonic Hh (Shh), Indian Hh (Ihh), and Desert Hh (Dhh), but only a single Hh protein is present in Drosophila. Shh is essential for normal development of the nervous system, skeleton, and limbs (3). Ihh and Dhh are required for normal skeletal and testis development, respectively (5, 6). Hh proteins also play a role in maintenance and regeneration of adult tissues and stem cells (7,8), and abnormal Hh signaling has been implicated in several cancers (9). Drugs targeting the Hh pathway are currently in late stage clinical trials for the treatment of basal cell carcinoma (10) and early stage trials for treatment of breast, pancreatic, ovarian, brain, and gastric cancers (10, 11).Hh distribution and responsiveness are tightly regulated, and many factors influence the secretion, movement, and reception of Hh signals (12, 13). Hh proteins are synthesized as 45-kDa precursors that cleave themselves to generate an N-terminal 19-kDa fragment (HhN) and a C-terminal 25-kDa fragment (HhC). HhC mediates this reaction, which also results in the covalent attachment of cholesterol to the C terminus of HhN (14). HhN is palmitoylated at its N terminus in a separate reaction, and dually lipidated HhN is secreted as part of a multivalent lipoprotein particle (13,15). HhN mediates all known Hh signaling activities, and HhN lipidation and multivalency are required both for full potency and to regulate the distribution of HhN (12). Reception of the Hh signal involves Patched (Ptc) (16), a 12-pass integral membrane protein with homology to proton-driven bacterial transporters, and Smoothened (17), a 7-pass integral membrane protein with homology to G-protein coupled receptors. In the absence of Hh, Ptc inhibits the activity of Smoothened (17). Hh relieves this inhibition, resulting in the activation of Smoothened and downstream effectors that converge on Gli family transcription factors to alter expression levels of target genes (17).Despite high sequence similarity between Hh proteins, not all interactions between Hh proteins and cell-surface receptors are conserved between vertebrates and invertebrates. Vertebrate Hh proteins appear to interact directly with cognate Ptc proteins, but a direct interaction between the N-terminal signaling domai...

Background: An asymmetric dimer of ErbB kinases in which one kinase activates the other is essential for ErbB activity. Results: A hierarchy of ErbB kinase activator-receiver preferences is mediated by intracellular regions. Conclusion: Intracellular ErbB asymmetry shapes signaling output from ErbB heterodimers but is not coupled to extracellular asymmetry. Significance: The signaling output from an ErbB varies with different partners and ligands.