Abstract
Contactin-4 (CNTN4) is a complex cell adhesion molecule (CAM) localized at neuronal membranes, playing a key role in maintaining the mechanical integrity and signaling properties of the synapse. CNTN4 consists of six immunoglobulin C2 type (IgC2) domains and four fibronectin type III (FnIII) domains that are shared with many other CAMs. Mutations in CNTN4 gene have been linked to various psychiatric disorders. Toward elucidating the response of this modular protein to mechanical stress, we studied its force-induced unfolding using single molecule atomic force microscopy (smAFM) and steered molecular dynamics (SMD) simulations. Extensive smAFM and SMD data both indicate the distinctive mechanical behavior of the two types of modules distinguished by unique force-extension signatures. The data also reveal the heterogeneity of the response of the individual FNIII and IgC2 modules, which presumably plays a role in the adaptability of CNTN4 to maintaining cell-cell communication and adhesion properties under different conditions. Results show that extensive sampling of force spectra, facilitated by robot-enhanced AFM, can help reveal the existence of weak stabilizing interactions between the domains of multidomain proteins, and provide insights into the nanomechanics of such multidomain or heteromeric proteins.
Highlights
Contactin-4 (CNTN4) is a complex cell adhesion molecule (CAM) localized at neuronal membranes, playing a key role in maintaining the mechanical integrity and signaling properties of the synapse
The stressstrain curves obtained by single molecule atomic force microscopy (smAFM) experiments for CNTN4 exhibit a saw-tooth pattern where each tooth corresponds to the unfolding of a domain or its part (Fig. 2)
Recent studies indicate that the absence of CNTN4 or its binding partner APP49 in neuronal cells has an impact on target-specific axon arborization, which in turn affects functional development of a visual pathway[50]
Summary
Contactin-4 (CNTN4) is a complex cell adhesion molecule (CAM) localized at neuronal membranes, playing a key role in maintaining the mechanical integrity and signaling properties of the synapse. CNTNs are neuronal membrane proteins that belong to a subgroup of the immunoglobulin (Ig) superfamily of CAMs (IgCAMs) associated with the brain[4] They are involved in axonal growth, guidance and fasciculation[5], in addition to linking pre- and postsynaptic cells. CNTN4s are tethered by a glycosylphosphatidylinositol (GPI)-linker to the pre-synaptic membrane[9,10]; and have several binding partners such as the amyloid precursor protein (APP), secreted APP ectodomain (APPsα), amyloid-like protein 1 (APLP1), and protein tyrosine phosphatase receptor γ (PTPRγ) In spite of their vital biological role, the properties and interactions of CNTNs at molecular level remain to be established[9]. The nanomechanics of CAMs remains to be established and this is a field of vigorous research[16,17,18]
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