Involvement of ERp44 and Ero‐L in the Maturation of Serotonin Transporter

Abstract

The serotonin transporter (SERT) is a glycoprotein responsible for the uptake of extracellular serotonin [(5‐hydroxytryptamine (5HT)] and has been attributed to disorders such as obsessive‐compulsive, depression, and primary pulmonary hypertension. Furthermore, it has been shown that SERT assembles into higher order complexes and functions most favorably in oligomeric form. However, while glycosylation by sialic acid has been shown to facilitate SERT oligomerization, no additional mediators of SERT oligomerization have yet been identified. In our current study, we have identified ERp44, a novel endoplasmic reticulum chaperone involved in thiol‐mediated retention, which colocalizes and binds to SERT. However, the SERT mutants, C200S or C209S could neither associate with ERp44 nor with each other. Based on our preliminary data we hypothesize that two critical, ER‐located chaperones, ERp44 and Ero1‐Lα? play a defined role in the assembly of SERT proteins in an oligomeric form via mediating the formation of an intramolecular disulfide bridge in the SERT protein backbond between C200 and C209 residues. Following the maturation, SERT proteins in an oligomeric form first dissociate from ERp44‐Ero1‐Lα ?complex and pass the ER quality control mechanism to enter the membrane trafficking pathway.