Heparan and chondroitin sulfate proteoglycans (HSPGs and CSPGs, respectively) regulate numerous cell surface signaling events, with typically opposite effects on cell function. CSPGs inhibit nerve regeneration through receptor protein tyrosine phosphatase sigma (RPTPs). Here we report that RPTPs acts bimodally in sensory neuron extension, mediating CSPG inhibition and HSPG growth promotion. Crystallographic analyses of a shared HSPG-CSPG binding site reveal a conformational plasticity that can accommodate diverse glycosaminoglycans with comparable affinities. Heparan sulfate and analogs induced RPTPs ectodomain oligomerization in solution, which was inhibited by chondroitin sulfate. RPTPs and HSPGs colocalize in puncta on sensory neurons in culture, whereas CSPGs occupy the extracellular matrix. These results lead to a model where proteoglycans can exert opposing effects on neuronal extension by competing to control the oligomerization of a common receptor.
Erythropoetin-producing hepatoma (Eph) receptors are cell surface protein tyrosine kinases mediating cell-cell communication. Upon activation they form signalling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2), alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD ). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across Aclass Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but re-arranged to accommodate ephrinA5 RBD . Cell surface expression of mutant EphA2s demonstrated that these interfaces are critical for localization at cellcell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions seed an arrangement of receptors which can propagate into extended signalling arrays.Ephs constitute a quarter of all known human receptor tyrosine kinases. They direct key processes during development and repair of the nervous system, blood vessel formation, insulin secretion, immune system function, intestinal homeostasis and bone tissue integrity 1 . They are grouped into two classes, A and B 2 , but domain composition is conserved across the family (Fig. 1a). The extracellular region comprises an N-terminal ligand-binding domain (LBD), a cysteine-rich region and two fibronectin type III domains (FN1 and FN2). FN2 connects to the transmembrane helix (TM), followed by an intracellular region comprising a juxtamembrane region (JM), a tyrosine kinase domain and a sterile-alpha motif (SAM) domain often linked to a C-terminal PDZ binding motif. Structures have been determined for examples of all Eph domains in isolation, with the exception of the cysteinerich region 3,4 .Activation of Eph receptors depends on the presence of their ligands (ephrins) and involves the packing of Ephs into signalling clusters 1,4 . Ephrins consist of an N-terminal extracellular receptor-binding domain (ephrin RBD ) and a C-terminal extension linked to the plasmamembrane by a lipid anchor (class A ephrins) or transmembrane helix (class B ephrins). Binding affinities vary for different Eph-ephrin pairs, but in general binding within classes is favoured 5 . Crystal structures for 1:1 complexes of Eph LBDs bound to ephrin RBD s show a hydrophobic ephrin-binding groove on the receptor and provide insight into ligand-receptor specificity, but do not define a mechanism for ligand-dependent signalling 6 . Members of the Correspondence and request for materials should be addressed to A.R.A (radu@strubi.ox.ac.uk) or E.Y.J. (yvonne@strubi.ox.ac.uk).. Author contributions E.S. conducted crystallographic and cellular studies. K.H. performed crystal mounting and oversaw X-ray data collection. G.S. led the MALS analysis. A.R.A. and E.Y.J. participated in study design and oversaw all aspects of the work. Author informationAtomic coordinates and structur...
The structure of the membrane-containing bacteriophage PRD1 has been determined by X-ray crystallography at about 4 A resolution. Here we describe the structure and location of proteins P3, P16, P30 and P31. Different structural proteins seem to have specialist roles in controlling virus assembly. The linearly extended P30 appears to nucleate the formation of the icosahedral facets (composed of trimers of the major capsid protein, P3) and acts as a molecular tape-measure, defining the size of the virus and cementing the facets together. Pentamers of P31 form the vertex base, interlocking with subunits of P3 and interacting with the membrane protein P16. The architectural similarities with adenovirus and one of the largest known virus particles PBCV-1 support the notion that the mechanism of assembly of PRD1 is scaleable and applies across the major viral lineage formed by these viruses.
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