SNX16 Regulates the Recycling of E-Cadherin through a Unique Mechanism of Coordinated Membrane and Cargo Binding

Abstract

E-Cadherin is a major component of adherens junctions on cell surfaces. SNX16 is a unique member of sorting nexins that contains a coiled-coil (CC) domain downstream of the PX domain. We report here that SNX16 regulates the recycling trafficking of E-cadherin. We solved the crystal structure of PX-CC unit of SNX16 and revealed a unique shear shaped homodimer. We identified a novel PI3P binding pocket in SNX16 that consists of both the PX and the CC domains. Surprisingly, we showed that the PPII/α2 loop, which is generally regarded as a membrane insertion loop in PX family proteins, is involved in the E-cadherin binding with SNX16. We then proposed a multivalent membrane binding model for SNX16. Our study postulates a new mechanism for coordinated membrane binding and cargo binding for SNX family proteins in general, and provide novel insights into recycling trafficking of E-cadherin.

Chromatin accessibility dynamics ofChlamydia-infected epithelial cells

“…The C. trachomatis effector protein, IncE, binds to sorting nexins 5 and 6, disrupting retromer-mediated host trafficking pathways [42] and potentially perturbing the endolysomalmediated bacterial destruction capacity of the host cell [43]. However, SNX16 is a unique member of this family, containing a coiled-coil domain in addition to a PX domain, and is not associated with retromer [44]. SNX16 is instead associated with the recycling and trafficking of E-cadherin [44], which mediates cell-cell adhesion in epithelial cells, and is associated with a diversity of tissue specific processes, including fibrosis and epithelial-mesenchymal transition (EMT) [45].…”

“…However, SNX16 is a unique member of this family, containing a coiled-coil domain in addition to a PX domain, and is not associated with retromer [44]. SNX16 is instead associated with the recycling and trafficking of E-cadherin [44], which mediates cell-cell adhesion in epithelial cells, and is associated with a diversity of tissue specific processes, including fibrosis and epithelial-mesenchymal transition (EMT) [45]. Separately, C. trachomatis infection has been shown to downregulate Ecadherin expression via increased promotor methylation, potentially contributing to EMT-like changes [46].…”

Higher order assembly of Sorting Nexin 16 controls tubulation and distribution of neuronal endosomes

“…Deleting a fragment containing CC domain results in hSNX16 loss from later endosomes and delays trafficking of internalized EGF (Hanson and Hong, 2003), highlighting the functional importance of the hSNX16 CC domain. Furthermore, structural studies reveal that PX and CC domains of SNX16 jointly contribute to entrance of PI(3)P into its binding pocket (Xu et al, 2017). Interestingly, two of the three key residues from the CC domain (E234, E235, and Y238) shaping this entrance map to E350 and E351 in dSNX16, which are mutated in dominant active mutant dSNX16 3A (Fig.…”

“…SNX16 has been implicated in regulating receptor traffic and signaling in both mammalian cells and in Drosophila (Choi et al, 2004b;Debaisieux et al, 2016;Hanson and Hong, 2003;Rodal et al, 2011). SNX16 contains a PX domain that binds specifically to PI(3)P, as well as a C-terminal coiled-coil (CC) domain, which is required for its selfassociation in vivo (Choi et al, 2004b;Hanson and Hong, 2003), and mediates dimerization in the SNX16 crystal structure (Xu et al, 2017). However, the mechanisms by which the CC domain contributes to the cellular functions of SNX16 are unknown.…”

“…Additional findings suggest an important role of the CC domain in SNX16 regulation. Human SNX16 (hSNX16) localizes to recycling and tubular late endosomes in addition to PI(3)P-rich early endosomes in immortalized cell lines (Brankatschk et al, 2011;Choi et al, 2004b;Hanson and Hong, 2003;Le Blanc et al, 2005;Xu et al, 2017;Zhang et al, 2013), suggesting that PI(3)P binding is not sufficient to explain its endosome association. Deleting a fragment containing CC domain results in hSNX16 loss from later endosomes and delays trafficking of internalized EGF (Hanson and Hong, 2003), highlighting the functional importance of the hSNX16 CC domain.…”