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Receptor-like role for PQLC2 amino acid transporter in the lysosomal sensing of cationic amino acids

Significance Cells sense and respond to nutrients liberated by the degradative activity of lysosomes. PQLC2 is a transporter that mediates the efflux of lysosomal cationic amino acids and also recruits a signaling complex containing WDR41, SMCR8, and C9orf72 proteins to the surface of lysosomes by interacting with WDR41. This interaction is regulated by the availability of the amino acids that PQLC2 transports. Here we define sites of contact between PQLC2 and WDR41 and relate them to conformational changes required for transport activity of PQLC2. In addition to directly advancing our understanding of the WDR41–PQLC2 interaction, this study provides a model for how a transporter can also serve as a sensor that recruits signaling proteins to the membrane where it resides. PQLC2, a lysosomal cationic amino acid transporter, also serves as a sensor that responds to scarcity of its substrates by recruiting a protein complex composed of C9orf72, SMCR8, and WDR41 to the surface of lysosomes. This protein complex controls multiple aspects of lysosome function. Although it is known that this response to changes in cationic amino acid availability depends on an interaction between PQLC2 and WDR41, the underlying mechanism for the regulated interaction is not known. In this study, we present evidence that the WDR41–PQLC2 interaction is mediated by a short peptide motif in a flexible loop that extends from the WDR41 β-propeller and inserts into a cavity presented by the inward-facing conformation of PQLC2. The data support a transceptor model wherein conformational changes in PQLC2 related to substrate transport regulate the availability of the WDR41-binding site on PQLC2 and mediate recruitment of the WDR41-SMCR8-C9orf72 complex to the surface of lysosomes.