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8.A.61 The Cornichon (CNIH) Family (formerly the Erv14 Family)

The yeast Nha1p Na+, K+/H+ antiporter has a house-keeping role in pH and cation homeostasis, being needed to alleviate excess Na+ or K+ from the cytoplasm under high external concentrations of these cations. Erv14p, a putative cargo receptor for transmembrane proteins, is required for trafficking of Nha1p from the endoplasmic reticulum to the plasma membrane. Sensitivity to high Na+ concentrations of the erv14 mutant relevant to the intracellular mislocalization of Nha1p-GFP, together with lower Na+ efflux, indicated the involvement of this mutual association to accomplish the survival of the yeast cell upon sodium stress (Rosas-Santiago et al. 2015). This observation is supported by the protein- protein interaction between Erv14p and Nha1p detected using two assays. These and other results indicated that even though Erv14p interacts with Nha1p through the TM domains, the C-terminus is important not only for the efficient delivery of Nha1p to the plasma membrane but also for its dimerization to accomplish its role in yeast salt tolerance.  Other functions of Erv14 involve regulation of export of the bud site, positioning of the axial growth site selection protein AXL2 and possibly other secretory proteins from the endoplasmic reticulum in COPII-coated vesicles. It seems to be required for the normal axial budding pattern in haploid cells (Powers and Barlowe 1998). 

Cornichon proteins are 160 - 180 aas in length and usually have 3 apparent, but 4 actual TMSs with the N-terminus in the cytoplasm (Nakagawa 2019).  They function as shuttles for the export of cargo proteins from the ER of eukaryotes to the plasma membrane. TMS 1 is not cleaved off. These auxiliary subunits control the building and gating of AMPARs (TC# 1.A.10) in the brain. The cryoEM structure has been determined in complex with a AMPA receptor (Nakagawa 2019).  CNIH2 and 3 are specialized for AMPARs (subunits GluA1 - 4)  and do not dissociate from them (Schwenk and Fakler 2019).  They slow deactivation and desensitization, prolonging the open state, enhancing the influx of Na+ and Ca2+. The other two auxilary subunits of AMPARs are the GSG1L (TC# 8.A.16.5) and the TARPs (TC# 8.A.16.2). GSG1L proteins also have 4 TMSs, but in a different arrangement.

References associated with 8.A.61 family:

Bökel, C., S. Dass, M. Wilsch-Bräuninger, and S. Roth. (2006). Drosophila Cornichon acts as cargo receptor for ER export of the TGFα-like growth factor Gurken. Development 133: 459-470. 16396907
Castro, C.P., D. Piscopo, T. Nakagawa, and R. Derynck. (2007). Cornichon regulates transport and secretion of TGFα-related proteins in metazoan cells. J Cell Sci 120: 2454-2466. 17607000
Hawken, N.M., E.I. Zaika, and T. Nakagawa. (2017). Engineering defined membrane-embedded elements of AMPA receptor induces opposing gating modulation by cornichon 3 and stargazin. J. Physiol. 595: 6517-6539. 28815591
Hoffman, J.L., S. Faccidomo, B.L. Saunders, S.M. Taylor, M. Kim, and C.W. Hodge. (2021). Inhibition of AMPA receptors (AMPARs) containing transmembrane AMPAR regulatory protein γ-8 with JNJ-55511118 shows preclinical efficacy in reducing chronic repetitive alcohol self-administration. Alcohol Clin Exp Res 45: 1424-1435. 34086361
Nakagawa, T. (2019). Structures of the AMPA receptor in complex with its auxiliary subunit cornichon. Science 366: 1259-1263. 31806817
Powers, J. and C. Barlowe. (1998). Transport of axl2p depends on erv14p, an ER-vesicle protein related to the Drosophila cornichon gene product. J. Cell Biol. 142: 1209-1222. 9732282
Rosas-Santiago P., Zimmermannova O., Vera-Estrella R., Sychrova H. and Pantoja O. (2016). Erv14 cargo receptor participates in yeast salt tolerance via its interaction with the plasma-membrane Nha1 cation/proton antiporter. Biochim Biophys Acta. 1858(1):67-74. 26440927
Rosas-Santiago, P., D. Lagunas-Gomez, C. Yáñez-Domínguez, R. Vera-Estrella, O. Zimmermannová, H. Sychrová, and O. Pantoja. (2017). Plant and yeast cornichon possess a conserved acidic motif required for correct targeting of plasma membrane cargos. Biochim. Biophys. Acta. 1864: 1809-1818. [Epub: Ahead of Print] 28723420
Schwenk, J. and B. Fakler. (2019). Folding unpredicted. Science 366: 1194-1195. 31806799
Wudick, M.M., M.T. Portes, E. Michard, P. Rosas-Santiago, M.A. Lizzio, C.O. Nunes, C. Campos, D. Santa Cruz Damineli, J.C. Carvalho, P.T. Lima, O. Pantoja, and J.A. Feijó. (2018). CORNICHON sorting and regulation of GLR channels underlie pollen tube Ca homeostasis. Science 360: 533-536. 29724955