Fig. 7. Diagrammatic representation of the proposed open and closed MHCI interactions in cis and trans that modulate neuritogenesis.

A) On the cell surface, closed MHCI (left) consisting of a heavy chain (α1, α2 and α3 domains shown in black), ϐ2M (grey rectangle) and a cytosolic peptide (stippled) can dissociate forming an open conformer (right). The free heavy chain’s cytoplasmic tail becomes phosphorylated (P) (reviewed in (Arosa et al., 2007)). B) The open conformers (center) can bind in cis to other free heavy chains, forming homodimers (left side), or associate with other cell surface molecules (such as insulin receptor, EGF receptor, IGF receptor, transferrin receptor, CD8αϐ and others), represented by a grey diamond) forming heterodimers (right side). We depict the open MHCI binding to a receptor through the heavy chain’s peptide-empty α1 and α2 domains based on the observations of Jelonek et al. Heterodimer formation modulates the receptor’s intracellular signaling in response to ligand binding and/or its internalization in ways that promote neurite outgrowth and neuronal polarization. C) Closed MHCI can bind classical MHCI receptors on same cell surface in cis preventing the receptor from interacting with MHCI on another cell (Back et al., 2009; Chalifour et al., 2009; Held and Mariuzza, 2008; Masuda et al., 2007) (left). Classical MHCI receptors that interact in trans with closed MHCIs on another cell surface send an inhibitory intracellular signal for axon outgrowth (center). Similarly, classical MHCI receptors can also bind soluble closed MHCI molecules that are shed from MHCI-expressing cells, which leads to inhibitory signals for axon outgrowth (Escande-Beillard et al., 2010; Washburn et al., 2011) (right side).