Sortilin 1

Sortilin (SORT1) is a protein that in humans is encoded by the SORT1 gene on chromosome 1.[5] This protein is a type I membrane glycoprotein in the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors. While it is ubiquitously expressed in many tissues,[6] sortilin is most abundant in the central nervous system.[7] At the cellular level, sortilin functions in protein transport between the Golgi apparatus, endosome, lysosome, and plasma membrane, leading to its involvement in multiple biological processes such as glucose and lipid metabolism as well as neural development and cell death.[8][9][10][11][12] Moreover, the function and role of sortilin is now emerging in several major human diseases such as hypertension, atherosclerosis, coronary artery disease, Alzheimer’s disease, and cancer.[13][14][15][16] The SORT1 gene also contains one of 27 loci associated with increased risk of coronary artery disease.[17]

SORT1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSORT1, Gp95, LDLCQ6, NT3, NTR3, Sortilin 1
External IDsOMIM: 602458 MGI: 1338015 HomoloGene: 136097 GeneCards: SORT1
Orthologs
SpeciesHumanMouse
Entrez

6272

20661

Ensembl

ENSG00000134243

ENSMUSG00000068747

UniProt

Q99523

Q6PHU5

RefSeq (mRNA)

NM_001205228
NM_002959

NM_001271599
NM_019972

RefSeq (protein)

NP_001192157
NP_002950

NP_001258528
NP_064356

Location (UCSC)Chr 1: 109.31 – 109.4 MbChr 3: 108.19 – 108.27 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

Gene

The SORT1 gene resides on chromosome 1 at the band 1p13.3 and includes 23 exons.[5] This gene encodes 2 isoforms through alternative splicing.[18]

Protein

Sortilin is a member of the Vps10p sorting receptor family.[7] Crystallization studies of the protein reveal that, when complexed with the ligand neurotensin, the Vps10 ectodomain of sortilin forms a ten-bladed beta-propeller structure with an inner tunnel that contains multiple ligand binding sites.[19] To prevent premature ligand binding during its synthesis, the precursor protein of sortilin contains a 44-amino acid pro-peptide that serves as a chaperone for the Vps10p domain.[20] In addition, two hydrophobic loops have been detected in this domain and act to anchor the protein in the cell membrane.[21] Sortilin has also been shown to undergo a conformational change and form a protein dimer in acidic conditions similar to ones found in the endosome, indicating a double mechanism for low pH-induced ligand release and possibly signaling towards recycling of the receptor. [22]

Function

In humans, sortilin is expressed over a wide range of cell types and tissues such as the brain, spinal cord, adrenal gland, thyroid, B-lymphocytes, adipocytes, skeletal muscle, and heart.[23] As a sorting receptor on the cell surface and on the endoplasmic reticulum-Golgi apparatus within the cell, sortilin is involved in the transport of a wide variety of intracellular proteins between the trans-Golgi network, endosome, lysosome, and secretory granules, as well as the plasma membrane.[8] This molecular function enables sortilin to participate in various biological processes, including the transport of GLUT4 to the plasma membrane of fat and skeletal muscle cells in response to insulin.[9] It also mediates the interaction between proNGF and the p75NTR:sortilin complex by acting as a co-receptor to signal cell death.[12][20] The fine regulation of the brain-derived neurotrophic factor (BDNF) by sortilin is required for both neuronal and tumor cell survival.[24] Moreover, sortilin has been implicated in LDL-cholesterol metabolism, VLDL secretion, and PCSK9 secretion, and thus plays a role in the development of atherosclerotic lesions.[10][11] It modulates lipid metabolism in adipocytes, hepatocytes, and macrophages.[25] Other processes involving sortilin include endocytosis,[8] negative regulation of lipoprotein lipase activity,[26] myotube differentiation,[27] ossification,[28] and regulation of gene expression.[27]

Clinical significance

Given its function in facilitating lysosomal degradation or recycling of ligands in lipid metabolism[11][14][29][30][31] and the neural system,[32] sortilin likely plays an important role in the underlying mechanisms and pathophysiology of atherogenesis and coronary artery disease, as well as in neurological disorders. For example, sortilin has been identified as an important receptor for brain apolipoprotein E (APOE) metabolism, which is implicated in the underlying mechanisms of Alzheimer’s disease.[32][33][34][35] A significant role for sortilin has recently also been reported in the field of oncology, as it has been detected in several cancer cell lines. Notably, human cancerous epithelial cells exhibited increased levels of sortilin as compared to normal epithelial tissues. Furthermore, it appears that sortilin participates in the progression of breast cancer and contributes to tumor cell adhesion and invasion.[15][16]

Clinical marker

In 2007, chromosome 1p13.3 was identified as a promising locus through a genome-wide approach in patients with coronary artery disease.[36] Subsequently, accumulating evidence suggests that the SORT1 gene at the 1p13 locus is an important risk factor for coronary artery disease, which is attributed to lipid metabolism disorders.[36][37][38] Several single nucleotide polymorphisms of the SORT1 gene have a genetic association between serum blood lipid levels and the pathogenesis of cardiometabolic syndrome, including obesity, hypertension, and coronary artery disease.[25] As the role of sortilin in lipid metabolism and the development of atherosclerosis has been established, a recent study further reported that increased release of soluble sortilin from platelets, measured as circulating sortilin, may be associated with in vivo platelet activation.[39] This observation also indicates that sortilin has a potential application as a clinical biomarker for diagnosis and prognosis.[10][39] Additionally, a multi-locus genetic risk score study, based on a combination of 27 loci including the SORT1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[17]

Interactions

Sortilin has been shown to interact with GGA1[40] and GGA2.[8][40]

Interactive Pathway Map

Sortilin participates in interactions within the trans-Golgi network vesicle budding and BDNF signaling pathways.

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000134243 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000068747 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: SORT1 sortilin 1".
  6. "BioGPS - your Gene Portal System". biogps.org. Retrieved 2016-08-16.
  7. Andersen JL, Schrøder TJ, Christensen S, Strandbygård D, Pallesen LT, García-Alai MM, et al. (February 2014). "Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor-ligand complex". Acta Crystallographica. Section D, Biological Crystallography. 70 (Pt 2): 451–460. doi:10.1107/S1399004713030149. PMC 3940197. PMID 24531479.
  8. Nielsen MS, Madsen P, Christensen EI, Nykjaer A, Gliemann J, Kasper D, et al. (May 2001). "The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein". The EMBO Journal. 20 (9): 2180–2190. doi:10.1093/emboj/20.9.2180. PMC 125444. PMID 11331584.
  9. Huang G, Buckler-Pena D, Nauta T, Singh M, Asmar A, Shi J, et al. (October 2013). "Insulin responsiveness of glucose transporter 4 in 3T3-L1 cells depends on the presence of sortilin". Molecular Biology of the Cell. 24 (19): 3115–3122. doi:10.1091/mbc.E12-10-0765. PMC 3784384. PMID 23966466.
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  11. Kjolby M, Nielsen MS, Petersen CM (April 2015). "Sortilin, encoded by the cardiovascular risk gene SORT1, and its suggested functions in cardiovascular disease". Current Atherosclerosis Reports. 17 (4): 496. doi:10.1007/s11883-015-0496-7. PMID 25702058. S2CID 22361357.
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  20. Nykjaer A, Willnow TE (April 2012). "Sortilin: a receptor to regulate neuronal viability and function". Trends in Neurosciences. 35 (4): 261–270. doi:10.1016/j.tins.2012.01.003. PMID 22341525. S2CID 28152980.
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