HSPA12A targets the cytoplasmic domain and affects the trafficking of the Amyloid Precursor Protein receptor SorLA

SorLA and Sortilin are multifunctional receptors involved in endocytosis and intracellular sorting of different and unrelated ligands. SorLA has recently attracted much attention as a novel strong risk gene for Alzheimer's disease, and much effort is currently being put into understanding the underlying molecular mechanism. Trafficking of SorLA and Sortilin are mediated by interacting with AP-1, AP-2, GGA 1-3 and the retromer complex. Although these cytosolic adaptor proteins all bind to both SorLA and Sortilin, a large fraction of intracellular Sortilin and SorLA are located in different subcellular vesicles. This indicates that unknown specialised adaptor proteins targeting SorLA for trafficking are yet to be discovered. We have identified HSPA12A as a new adaptor protein that, among Vps10p-D receptors, selectively binds to SorLA in an ADP/ATP dependent manner. This is the first described substrate of HSPA12A, and we demonstrate that the binding, which affects both endocytic speed and subcellular localisation of SorLA, is mediated by specific acidic residues in the cytosolic domain of SorLA. The identification of the relatively unknown HSPA12A as a SorLA specific interaction partner could lead to novel insight into the molecular mechanism of SorLA, and re-emphasises the role of heat shock proteins in neurodegenerative diseases.