SORT1 Membrane Protein Introduction

Introduction of SORT1

Sortilin is a 100 kDa transmembrane protein encoded by the SORT1 gene, which was first identified in human brain tissue in 1997. Sortilin belongs to the vacuolar protein sorting 10 (Vps10p) family. There are five members of this family, including Sortilin, Sorting Protein Associated Receptor and Type A Repeat (SorLA), Sortilin Associated Receptors SorCS1, SorCS2, and SorCS3. Sortilin consists of an N-terminal signal peptide (1-33 aa), a propeptide (34-78 aa), a Vps10p domain (133-741 aa), ca transmembrane helix (759-780 aa), and an intracellular C-terminal tail (781-831 aa). The extracellular Vps10p domain and intracellular tail are highly conserved in evolution. The Vps10p domain is formed by folding 10 cysteine-rich fragments that appear to be arranged in a tunnel shape with a unique 10-blade beta-propeller that can serve as a ligand-binding channel. The Vps10p domain contains two lysosomal sorting motifs, MS1 (787-FLVHRY-792) and MS2 (823-HDDSDEDLL-831). In addition to being widely expressed in the CNS, sortilin is also expressed in various types of peripheral cells, including hepatocytes, adipocytes, skeletal muscle cells, and macrophages.

Function of SORT1 Membrane Protein

As an important membrane signaling protein, sortilin binds to a large number of ligands expressed in the central and peripheral cells. Most of the sortilin ligands identified to date are associated with lipid metabolism or neurotrophin signaling. Ligands associated with lipid metabolism include lipoprotein lipase, apolipoprotein A-V (Apo A-V) and ApoB100, which are typically transported to the cell surface by constitutive secretions and then degraded in lysosomes. The neurotrophic signaling pathway is complex, and sortilin participates in signaling transport via three different ways. First, with the help of sortilin, mature neurotrophic factor (mNT) is released into the extracellular space by a pro-neurotrophic factor (proNT) by regulating the secretory pathway. Second, sortilin transports the tyrosine kinase receptor (Trk) to the axonal end by antegrade transport. Third, on the cell surface, sortilin and the neurotrophin receptor (p75^NTR) act as partners of proNT transduction for mediating apoptosis under differentiation, senescence, and certain pathological conditions. In addition, sortilin can bind to thyroglobulin and plays a role in the recycling of the latter. Sortilin is also involved in the formation of glucose transporter-4 (Glut4) vesicles, which regulate glucose transport in response to insulin. In conclusion, sortilin is transmitted between the cell surface and the endoplasmic reticulum, Golgi and lysosomes, mediating the different signal transduction, secretion, and degradation of various chaperone proteins, thereby fundamentally affecting their biological functions.

Fig.1 Molecular structure of the Vps10p receptor family of proteins. The extracellular domain of all receptors contains a Vps10p domain (Vps10p-D). (Xu, 2018)

Application of SORT1 Membrane Protein Literature

1. Xu S.Y., et al. Sortilin: a new player in dementia and Alzheimer-type neuropathology. Biochemistry and cell biology. 2018, 96(5): 491-497. PubMed ID: 29687731
   
   

   This study indicates that Vps10p member sortilin has been shown to be involved in amyloid plaque formation, abnormal protein sorting and apoptosis, which may provide a new basis for the development of Alzheimer's disease therapy.

2. Zhou F.Q., et al. Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer’s disease model mice and macaques. Alzheimers Research & Therapy. 2018, 10(1): 40. PubMed ID: 29690919
   
   

   This article demonstrates that neuritic plaques seen in the brains of transgenic AD model mice represent an incomplete form of the AD pathology marker in humans, indicating the presence of species differences in neuritic plaque components.

3. Hagita S., et al. Transcriptional control of intestinal cholesterol absorption, adipose energy expenditure and lipid handling by Sortilin. Scientific Reports. 2018, 8(1): 9006. PubMed ID: 29899496
   
   

   The results of this study demonstrate the novel role of sortilin in energy regulation and lipid homeostasis in female mice, which may be potential therapeutic targets for obesity and cardiovascular disease.

4. Hallee S., et al. The malaria parasite Plasmodium falciparum Sortilin is essential for merozoite formation and apical complex biogenesis. Cellular Microbiology. 2018, 20(8): e12844. PubMed ID: 29582546
   
   

   This article finds that sortilin in the Plasmodium falciparum has a wider range of functions compared with most other eukaryotes.

5. Goettsch C., et al. Sortilin and Its Multiple Roles in Cardiovascular and Metabolic Diseases. Arteriosclerosis Thrombosis & Vascular Biology. 2018, 38(1): 19-25. PubMed ID: 29191923
   
   

   This article comprehensively reviews the contribution of sortilin to cardiovascular and metabolic diseases and finds that sortilin may be a biomarker of cardiovascular risk, which can serve as a potential drug target.

SORT1 Preparation Options

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Reference

1. Xu S Y, et al. (2018). Sortilin: a new player in dementia and Alzheimer-type neuropathology. Biochemistry and cell biology. 96(5): 491-497.

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