Abstract
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.
Highlights
SorLA is a multifunctional receptor involved in endocytosis and intracellular sorting of different and unrelated ligands
The cd contains several motifs for binding of cytoplasmic adaptor proteins (e.g., Adaptor protein complexes-1 and -2 (AP), Golgi-localising, Gamma-adaptin ear domain homology, ARF-binding proteins 1 to 3 (Golgi-localising, Gamma-adaptin ear domain homology, ARF-binding proteins) and elements of the retromer complex) involved in receptor trafficking[7,8]. While 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, indicating that more yet unrecognised adaptor proteins are involved in the trafficking and localisation of SorLA and Sortilin[7]
Since MPR46 and MPR300 are shuttled between trans-Golgi network (TGN) and endosomes by the same mechanism as Sortilin and SorLA, the cd’s of both receptors were tested in Y2H against both HSPA12-A and -B
Summary
SorLA is a multifunctional receptor involved in endocytosis and intracellular sorting of different and unrelated ligands. The family is characterised by an N-terminal Vps10p domain, a unique 10-bladed β-propeller domain with ligand binding capacity[3], and a short cytoplasmic domain (cd) that mediate cellular trafficking through interaction with cytosolic adaptor proteins. The HSP70 protein family, encoded by 17 genes[22], is mainly involved in ATP-driven refolding and solubilisation of aggregated proteins[20]. The proteins HSPA12A and HSPA12B are distant members of the HSP70 family mainly due to an atypical ATP-binding domain[24]. Like SorLA, HSP70 proteins play an important role in neurodegenerative diseases, where they are involved in preventing protein misfolding and inhibiting aggregation
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