Breaking the rules of SLC6 transporters: Export of the human creatine transporter ‐1 from the endoplasmic reticulum is supported by its N‐terminus

Point mutations in the human creatine transporter 1 (CRT1) trigger the creatine transporter deficiency syndrome manifested by intellectual disability and epilepsy. Such pathogenic variants frequently impair CRT1 protein folding and trafficking. By generating serial truncations and chimeric constructs, we identified the amino-terminus region as a key determinant of endoplasmic reticulum (ER)-exit mechanisms of CRT1. Surprisingly, mutations in the putative carboxyl-terminal ER-export motifs failed to impair the delivery of CRT1 to the plasma membrane. Thus, CRT1 is unique among its solute carrier 6 transporter relatives, since the ER-export motif harbored in its amino-terminal domain overrides the canonical carboxyl-terminal sites. AbstractMutations in the human creatine transporter 1 (CRT1/SLC6A8) cause the creatine transporter deficiency syndrome, which is characterized by intellectual disability, epilepsy, autism, and developmental delay. The vast majority of mutations cause protein misfolding and hence reduce cell surface expression. Hence, it is important to understand the molecular machinery supporting folding and export of CRT1 from the endoplasmic reticulum (ER). All other SLC6 members thus far investigated rely on a C-terminal motif for binding the COPII-component SEC24 to drive their ER export; their N-termini are dispensable. Here, we show that, in contrast, in CRT1 the C-terminal ER-export motif is cryptic and it is the N-terminus, which supports ER export. This con...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research