Sortilin/Neurotensin Receptor 3: Three-dimensional Insights on its Coding Variants

Abstract

Introduction: Sortilin is a multifunctional sorting receptor required for Golgi-to-lysosome protein transport by a M-6-P independent pathway. It presents a unique structural organization with a 10-bladed β-propeller domain forming a tunnel where several ligands bind and is able to mediate the lysosomal targeting of sphingolipid activator proteins (SAPs), acid sphingomyelinase (AS) and cathepsins D and H. For some of these proteins no alternative receptor is known. The inner rim of the tunnel, along with several patches which function as additional binding sites have particularly high sequence conservation. Such structural organization is a key element for regulation of sortilin’s function and any sequence alterations changing it may potentially result in impaired lysosomal transport. As a result from the “1000Genomes Project”, several coding variants were identified for this protein with no known individuals carrying two of those variant alleles ever identified. Methods: In silico mutagenesis of sortilin was performed with SwissModelServer and the effect of each variant on its 3-dimensional structure was evaluated. The results were cross-linked with the potential pathogenicity predictions of PolyPhen and SIFT. Results/Discussion: Here we present the complete results of this in silico analysis, highlighting the potential of each one to disrupt sortilin’s structure and, consequently, impair its biological function and, ultimately, cause lysosomal storage and disease.