Contactin-associated protein-like 2 (CNTNAP2) is a large multidomain neuronal adhesion molecule implicated in a number of neurological disorders, including epilepsy, schizophrenia, autism spectrum disorder, intellectual disability, and language delay. We reveal here by electron microscopy that the architecture of CNTNAP2 is composed of a large, medium, and small lobe that flex with respect to each other. Using epitope labeling and fragments, we assign the F58C, L1, and L2 domains to the large lobe, the FBG and L3 domains to the middle lobe, and the L4 domain to the small lobe of the CNTNAP2 molecular envelope. Our data reveal that CNTNAP2 has a very different architecture compared with neurexin 1␣, a fellow member of the neurexin superfamily and a prototype, suggesting that CNTNAP2 uses a different strategy to integrate into the synaptic protein network. We show that the ectodomains of CNTNAP2 and contactin 2 (CNTN2) bind directly and specifically, with low nanomolar affinity. We show further that mutations in CNTNAP2 implicated in autism spectrum disorder are not segregated but are distributed over the whole ectodomain. The molecular shape and dimensions of CNTNAP2 place constraints on how CNTNAP2 integrates in the cleft of axo-glial and neuronal contact sites and how it functions as an organizing and adhesive molecule.

Background: Calsyntenin-3 (Cstn3) promotes synapse development, controversially interacting with neurexin 1␣ (n1␣). Results: Cstn3 binds n1␣ directly, and its structure adopts multiple forms. Conclusion: Cstn3 interacts with n1␣ via a novel mechanism and can produce distinct trans-synaptic bridges with n1␣. Significance: A complex portfolio of molecular interactions between proteins implicated in autism spectrum disorder and schizophrenia guide synapse development.

Results. Of the 90 colleges and schools of pharmacy that completed the survey, 7 colleges and schools did not currently have someone teaching pharmacoeconomics (eg, new school or looking for instructor). For the 83 colleges and schools that had an instructor who taught pharmacoeconomics, 69 covered pharmacoeconomic-related topics in a required course only; 5, in an elective course only; and 9, in both a required and elective course. The number of hours of pharmacoeconomic-related topics presented in required courses ranged from 1 to 48 hours (mean 5 21 6 14; median 5 19). Conclusions. Pharmacoeconomics education courses are offered at the majority of US colleges and schools of pharmacy. There was a wide range of hours devoted to pharmacoeconomic-related topics and the topics covered in these colleges and schools varied. Although the majority of US colleges and schools of pharmacy offer pharmacoeconomics courses, official guidelines are needed for the specific aspects and topics that should be covered in the classroom.

α-Neurexins are synaptic organizing molecules implicated in neuropsychiatric disorders. They bind and arrange an array of different partners in the synaptic cleft. The extracellular region of neurexin 1α (n1α) contains six LNS domains (L1-L6) interspersed by three Egf-like repeats. N1α must encode highly evolved structure-function relationships in order to fit into the narrow confines of the synaptic cleft, and also recruit its large, membrane-bound partners. Internal molecular flexibility could provide a solution, however, it is challenging to delineate because currently no structural methods permit high resolution structure determination of large, flexible, multi-domain protein molecules. To investigate the structural plasticity of n1α, in particular the conformation of domains that carry validated binding sites for different protein partners, we used a panel of structural techniques. Individual particle electron tomography (IPET) revealed that the N-terminally and C-terminally tethered domains, L1 and L6, have a surprisingly limited range of conformational freedom with respect to the linear central core containing L2 through L5. A 2.8 Å crystal structure revealed an unexpected arrangement of the L2 and L3 domains. SAXS and ET indicated that incorporation of the alternative splice insert SS6 relieves the restricted conformational freedom between L5 and L6, suggesting that SS6 may work as a molecular toggle. The architecture of n1α thus encodes a combination of rigid and flexibly tethered domains that are uniquely poised to work together to promote its organizing function in the synaptic cleft, and may permit allosterically regulated and/or concerted protein partner binding.