2.A.1.53.3
The MFSD1 (SMAP4) transporter (465 aas; 12 TMSs).  Expression is increased in mice by amino acid starvation and decreased by a high fat diet (Perland et al. 2016). This lysosomal transporter is essential for liver homeostasis and critically depends on its accessory subunit GLMP (Massa López et al. 2019). MFSD1 is not N-glycosylated but contains a dileucine-based sorting motif needed for its transport to lysosomes. Mfsd1 knockout mice develop splenomegaly and severe liver disease. GLMP (406 aas and at least 2 TMSs, N- and C-terminal) physically interacts with MFSD1 and is a critical accessory subunit. GLMP is essential for the maintenance of normal levels of MFSD1 in lysosomes and vice versa. Glmp knockout mice mimic the phenotype of Mfsd1 knockout mice (Massa López et al. 2019).  The two lysosomal integral membrane proteins MFSD1 and GLMP form a tight complex that confers protection of both interaction partners against lysosomal proteolysis. López et al. 2020 refined the molecular interaction of the two proteins and found that the luminal domain of GLMP alone, but not its transmembrane domain or its short cytosolic tail, conveys protection and mediates the interaction with MFSD1. The interaction is essential for the stabilization of the complex. N-glycosylation of GLMP is essential for protection. The interaction of both proteins   starts in the endoplasmic reticulum, and quantitatively depends on each other. Both proteins can affect their intracellular trafficking to lysosomes. MFSD1 can form homodimers both in vitro and in vivo (López et al. 2020). MFSD1 facilitates highly selective dipeptide transport in lysosomes (Boytsov et al. 2024).