Sortilin

Sortilin is a type I transmembrane protein encoded by the SORT1 gene in humans. It belongs to the Vps10p-domain receptor family and functions as a sorting receptor that governs intracellular trafficking between the trans-Golgi network, endosomes, and lysosomes. The protein is widely expressed, with notable levels in the brain, liver, and adipose tissue, reflecting diverse roles in cellular transport and signaling.

Structurally, sortilin contains a luminal VPS10P domain responsible for cargo binding and a single spanning membrane segment with a cytoplasmic tail that contains sorting signals. This organization enables it to bind a variety of ligands in the lumen and direct them along endosomal-lysosomal or secretory pathways.

Sortilin participates in the trafficking of numerous cargoes, acting as a receptor for neurotrophins such as pro-nerve growth factor (proNGF) and possibly other neurotrophic factors, as well as for neurotensin. It also plays a key role in the intracellular handling of progranulin, promoting its transport to lysosomes and facilitating its degradation. Through these interactions, sortilin influences neuronal survival, growth factor signaling, and lysosomal function.

Genetic and functional studies link SORT1 to lipid metabolism and cardiovascular risk. Variants at SORT1 are associated with plasma levels of low-density lipoprotein cholesterol and may affect hepatic production and secretion of apolipoproteins and lipoprotein particles. In the nervous system, altered sortilin activity can modulate progranulin availability, with potential implications for neurodegenerative diseases such as frontotemporal dementia.

Due to its involvement in diverse trafficking pathways, sortilin is a subject of research in neurobiology, metabolism, and lysosome biology, with interest in targeting its interactions for therapeutic ends.