Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis.
Receptor protein tyrosine phosphatase sigma (RPTPσ) regulates neuronal extension and acts as a presynaptic nexus for multiple protein and proteoglycan interactions during synaptogenesis. Unknown mechanisms govern the shift in RPTPσ function, from outgrowth promotion to synaptic organization. Here, we report crystallographic, electron microscopic and small-angle X-ray scattering analyses, which reveal sufficient inter-domain flexibility in the RPTPσ extracellular region for interaction with both cis (same cell) and trans (opposite cell) ligands. Crystal structures of RPTPσ bound to its postsynaptic ligand TrkC detail an interaction surface partially overlapping the glycosaminoglycan-binding site. Accordingly, heparan sulphate and heparin oligomers compete with TrkC for RPTPσ binding in vitro and disrupt TrkC-dependent synaptic differentiation in neuronal co-culture assays. We propose that transient RPTPσ ectodomain emergence from the presynaptic proteoglycan layer allows capture by TrkC to form a trans-synaptic complex, the consequent reduction in RPTPσ flexibility potentiating interactions with additional ligands to orchestrate excitatory synapse formation.
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Charlotte H
CH
Coles
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Nikolaos
N
Mitakidis
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada V6T 2B5.
Peng
P
Zhang
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Jonathan
J
Elegheert
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Weixian
W
Lu
Cancer Section, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
Andrew W
AW
Stoker
Department of Molecular Physiology and Biophysics, Vanderbilt University, School of Medicine, 702 Light Hall (0615), Nashville, Tennessee 37232-0615, USA.
Terunaga
T
Nakagawa
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada V6T 2B5.
Ann Marie
AM
Craig
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
E Yvonne
EY
Jones
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
A Radu
AR
Aricescu
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002642:Chick Embryo; D018920:Coculture Techniques; D003460:Crystallization; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D008024:Ligands; D051379:Mice; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000737:chemistry / Q000502:physiology; D020812:Receptor, trkC / Q000737:chemistry / Q000502:physiology; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000737:chemistry* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000502:physiology*
D016326:Extracellular Matrix Proteins; D008024:Ligands; D011509:Proteoglycans; D020812:Receptor, trkC; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2