Speculation on How RIC-3 and Other Chaperones Facilitate alpha 7 Nicotinic Receptor Folding and Assembly

The process of how multimeric transmembrane proteins fold and assemble in the endoplasmic reticulum is not well understood. The alpha7 nicotinic receptor (alpha 7 nAChR) is a good model for multimeric protein assembly since it has at least two independent and specialized chaperones: Resistance to Inhibitors of Cholinesterase 3 (RIC-3) and Nicotinic Acetylcholine Receptor Regulator (NACHO). Recent cryo-EM and NMR data revealed structural features of alpha 7 nAChRs. A ser-ala-pro (SAP) motif precedes a structurally important but unique "latch" helix in alpha 7 nAChRs. A sampling of alpha 7 sequences suggests the SAP motif is conserved from C. elegans to humans, but the latch sequence is only conserved in vertebrates. How RIC-3 and NACHO facilitate receptor subunits folding into their final pentameric configuration is not known. The artificial intelligence program AlphaFold2 recently predicted structures for NACHO and RIC-3. NACHO is highly conserved in sequence and structure across species, but RIC-3 is not. This review ponders how different intrinsically disordered RIC-3 isoforms from C. elegans to humans interact with alpha 7 nAChR subunits despite having little sequence homology across RIC-3 species. Two models from the literature about how RIC-3 assists alpha 7 nAChR assembly are evaluated considering recent structural information about the receptor and its chaperones.