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Establishment of correct synaptic connections is a crucial step during neural circuitry formation. The Teneurin family of neuronal transmembrane proteins promotes cell–cell adhesion via homophilic and heterophilic interactions, and is required for synaptic partner matching in the visual and hippocampal systems in vertebrates. It remains unclear how individual Teneurins form macromolecular cis‐ and trans‐synaptic protein complexes. Here, we present a 2.7 Å cryo‐EM structure of the dimeric ectodomain of human Teneurin4. The structure reveals a compact conformation of the dimer, stabilized by interactions mediated by the C‐rich, YD‐shell, and ABD domains. A 1.5 Å crystal structure of the C‐rich domain shows three conserved calcium binding sites, and thermal unfolding assays and SAXS‐based rigid‐body modeling demonstrate that the compactness and stability of Teneurin4 dimers are calcium‐dependent. Teneurin4 dimers form a more extended conformation in conditions that lack calcium. Cellular assays reveal that the compact cis‐dimer is compatible with homomeric trans‐interactions. Together, these findings support a role for teneurins as a scaffold for macromolecular complex assembly and the establishment of cis‐ and trans‐synaptic interactions to construct functional neuronal circuits. Synopsis: Teneurin‐family transmembrane proteins promoting homo‐ and heterophilic neuronal interactions are important for synaptic partner matching. Here, structural studies of the dimeric human Teneurin4 ectodomain reveal a compact conformation compatible with homomeric trans interactions. 2.7 Å cryo‐EM structure reveals a compact calcium‐stabilized conformation of the Teneurin4 dimer ectodomain.Crystal structure of the C‐rich domain shows three calcium ions coordinated by conserved residues.Teneurin4 can change its conformation in cis from an extended form to a more compact one.The compact Teneurin4 dimer supports homomeric cell‐cell interactions. [ABSTRACT FROM AUTHOR]

Teneurins are ancient cell-cell adhesion receptors that are vital for brain development and synapse organisation. They originated in early metazoan evolution through a horizontal gene transfer event when a bacterial YD-repeat toxin fused to a eukaryotic receptor. We present X-ray crystallography and cryo-EM structures of two Teneurins, revealing a ~200 kDa extracellular super-fold in which eight sub-domains form an intricate structure centred on a spiralling YD-repeat shell. An alternatively spliced loop, which is implicated in homophilic Teneurin interaction and specificity, is exposed and thus poised for interaction. The Nterminal side of the shell is 'plugged' via a fibronectin-plug domain combination, which defines a new class of YD proteins. Unexpectedly, we find that these proteins are widespread amongst modern bacteria, suggesting early metazoan receptor evolution from a distinct class of proteins, which today includes both bacterial proteins and eukaryotic Teneurins. [ABSTRACT FROM AUTHOR]

Our nervous system depends on protein‐mediated cellular communication and connections for its formation and function. The transmembrane receptor Myelin‐Associated Glycoprotein (MAG) plays an important role in the wrapping process of myelin around axons and in life‐long maintenance of this important bicellular structure. MAG organizes the adhesion and the signalling between the axon and the myelin. But how does MAG do this? Better understanding of this process is required to treat MAG‐function associated neurological disorders. This editorial highlights a study by Myllykoski et al. in the current issue of the Journal of Neurochemistry that describes the identification and characterization of a novel intracellular binding partner of MAG. Using cellular, biophysical and structural techniques, the authors show that the dynein light chain, DYNLL1 recognizes and interacts with only one of two splice forms of MAG, L‐MAG. DYNLL1 dimerizes L‐MAG at the cytosolic side and this has implications for the signalling and adhesive functions of MAG in our nervous system. The integrity and function of the nervous system relies on myelin that is wrapped around axons. The myelin‐associated glycoprotein MAG has a role in myelin formation and function by organizing signaling and adhesion between myelin and axons. This editorial highlights a study by Myllykoski et al. in which a new factor, DYNLL1, has been identified that binds one of the two splice forms of MAG at the cytosolic side. The implications of this finding on a role in the adhesion and signalling properties of MAG are described here. [ABSTRACT FROM AUTHOR]

Co-receptors add complexity to cell-cell signaling systems. The secreted semaphorin 3s (Sema3s) require a co-receptor, neuropilin (Nrp), to signal through plexin As (PlxnAs) in functions ranging from axon guidance to bone homeostasis, but the role of the co-receptor is obscure. Here we present the low-resolution crystal structure of a mouse semaphorin-plexin-Nrp complex alongside unliganded component structures. Dimeric semaphorin, two copies of plexin and two copies of Nrp are arranged as a dimer of heterotrimers. In each heterotrimer subcomplex, semaphorin contacts plexin, similar to in co-receptor-independent signaling complexes. The Nrp1s cross brace the assembly, bridging between sema domains of the Sema3A and PlxnA2 subunits from the two heterotrimers. Biophysical and cellular analyses confirm that this Nrp binding mode stabilizes a canonical, but weakened, Sema3-PlxnA interaction, adding co-receptor control over the mechanism by which receptor dimerization and/or oligomerization triggers signaling. [ABSTRACT FROM AUTHOR]

Olfactomedin-1 (Olfm1; also known as noelin and pancortin) is a member of the olfactomedin domain-containing superfamily and a highly expressed neuronal glycoprotein important for nervous system development. It binds a number of secreted proteins and cell surface-bound receptors to induce cell signaling processes. Using a combined approach of x-ray crystallography, solution scattering, analytical ultracentrifugation, and electron microscopy we determined that full-length Olfm1 forms disulfide- linked tetramers with a distinctive V-shaped architecture. The base of the "V" is formed by two disulfide-linked dimeric N-terminal domains. Each of the two V legs consists of a parallel dimeric disulfide-linked coiled coil with a C-terminal β-propeller dimer at the tips. This agrees with our crystal structure of a C-terminal coiled-coil segment and β-propeller combination (Olfm1coil-Olf) that reveals a disulfide-linked dimeric arrangement with the β-propeller top faces in an outward exposed orientation. Similar to its family member myocilin, Olfm1 is stabilized by calcium. The dimer-of-dimers architecture suggests a role for Olfm1 in clustering receptors to regulate signaling and sheds light on the conformation of several other olfactomedin domain family members. [ABSTRACT FROM AUTHOR]