Sortilin 1 Explained

Sortilin (SORT1) is a protein that in humans is encoded by the SORT1 gene on chromosome 1.[1] 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,[2] sortilin is most abundant in the central nervous system.[3] 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.[4] [5] [6] [7] [8] 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.[9] [10] [11] [12] The SORT1 gene also contains one of 27 loci associated with increased risk of coronary artery disease.[13]

Structure

Gene

The SORT1 gene resides on chromosome 1 at the band 1p13.3 and includes 23 exons. This gene encodes 2 isoforms through alternative splicing.[14]

Protein

Sortilin is a member of the Vps10p sorting receptor family.[3] 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.[15] 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.[16] In addition, two hydrophobic loops have been detected in this domain and act to anchor the protein in the cell membrane.[17] 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. [18]

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.[19] 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.[4] 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.[5] It also mediates the interaction between proNGF and the p75NTR:sortilin complex by acting as a co-receptor to signal cell death.[8] [16] The fine regulation of the brain-derived neurotrophic factor (BDNF) by sortilin is required for both neuronal and tumor cell survival.[20] 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.[6] [7] It modulates lipid metabolism in adipocytes, hepatocytes, and macrophages.[21] Other processes involving sortilin include endocytosis,[4] negative regulation of lipoprotein lipase activity,[22] myotube differentiation,[23] ossification,[24] and regulation of gene expression.[23]

Clinical significance

Given its function in facilitating lysosomal degradation or recycling of ligands in lipid metabolism[7] [10] [25] [26] [27] and the neural system,[28] 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.[28] [29] [30] [31] 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.[11] [12]

Clinical marker

In 2007, chromosome 1p13.3 was identified as a promising locus through a genome-wide approach in patients with coronary artery disease.[32] 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.[32] [33] [34] 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. 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.[35] This observation also indicates that sortilin has a potential application as a clinical biomarker for diagnosis and prognosis.[6] [35] 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).[13]

Interactions

Sortilin has been shown to interact with GGA1[36] and GGA2.[4] [36]

Interactive Pathway Map

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

See also

Further reading

Notes and References

  1. Web site: Entrez Gene: SORT1 sortilin 1.
  2. Web site: BioGPS - your Gene Portal System. biogps.org. 2016-08-16.
  3. Andersen JL, Schrøder TJ, Christensen S, Strandbygård D, Pallesen LT, García-Alai MM, Lindberg S, Langgård M, Eskildsen JC, David L, Tagmose L, Simonsen KB, Maltas PJ, Rønn LC, de Jong IE, Malik IJ, Egebjerg J, Karlsson JJ, Uppalanchi S, Sakumudi DR, Eradi P, Watson SP, Thirup S . 6 . 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 . February 2014 . 24531479 . 3940197 . 10.1107/S1399004713030149 .
  4. Nielsen MS, Madsen P, Christensen EI, Nykjaer A, Gliemann J, Kasper D, Pohlmann R, Petersen CM . 6 . 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 . May 2001 . 11331584 . 125444 . 10.1093/emboj/20.9.2180 .
  5. Huang G, Buckler-Pena D, Nauta T, Singh M, Asmar A, Shi J, Kim JY, Kandror KV . 6 . 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 . October 2013 . 23966466 . 3784384 . 10.1091/mbc.E12-10-0765 .
  6. Patel KM, Strong A, Tohyama J, Jin X, Morales CR, Billheimer J, Millar J, Kruth H, Rader DJ . 6 . Macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis . Circulation Research . 116 . 5 . 789–796 . February 2015 . 25593281 . 4602371 . 10.1161/CIRCRESAHA.116.305811 .
  7. Kjolby M, Nielsen MS, Petersen CM . Sortilin, encoded by the cardiovascular risk gene SORT1, and its suggested functions in cardiovascular disease . Current Atherosclerosis Reports . 17 . 4 . 496 . April 2015 . 25702058 . 10.1007/s11883-015-0496-7 . 22361357 .
  8. Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C, Kliemannel M, Schwarz E, Willnow TE, Hempstead BL, Petersen CM . 6 . Sortilin is essential for proNGF-induced neuronal cell death . Nature . 427 . 6977 . 843–848 . February 2004 . 14985763 . 10.1038/nature02319 . 4343450 . 2004Natur.427..843N .
  9. Varzideh F, Jankauskas SS, Kansakar U, Mone P, Gambardella J, Santulli G . Sortilin drives hypertension by modulating sphingolipid/ceramide homeostasis and by triggering oxidative stress . The Journal of Clinical Investigation . 132 . 3 . February 2022 . 35104807 . 8803317 . 10.1172/JCI156624 .
  10. Goettsch C, Hutcheson JD, Aikawa M, Iwata H, Pham T, Nykjaer A, Kjolby M, Rogers M, Michel T, Shibasaki M, Hagita S, Kramann R, Rader DJ, Libby P, Singh SA, Aikawa E . 6 . Sortilin mediates vascular calcification via its recruitment into extracellular vesicles . The Journal of Clinical Investigation . 126 . 4 . 1323–1336 . April 2016 . 26950419 . 4811143 . 10.1172/JCI80851 .
  11. Roselli S, Pundavela J, Demont Y, Faulkner S, Keene S, Attia J, Jiang CC, Zhang XD, Walker MM, Hondermarck H . 6 . Sortilin is associated with breast cancer aggressiveness and contributes to tumor cell adhesion and invasion . Oncotarget . 6 . 12 . 10473–10486 . April 2015 . 25871389 . 4496368 . 10.18632/oncotarget.3401 .
  12. Wilson CM, Naves T, Al Akhrass H, Vincent F, Melloni B, Bonnaud F, Lalloué F, Jauberteau MO . 6 . A new role under sortilin's belt in cancer . Communicative & Integrative Biology . 9 . 1 . e1130192 . 2016-02-01 . 27066187 . 4802778 . 10.1080/19420889.2015.1130192 .
  13. Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield M, Devlin JJ, Nordio F, Hyde C, Cannon CP, Sacks F, Poulter N, Sever P, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS . 6 . Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials . Lancet . 385 . 9984 . 2264–2271 . June 2015 . 25748612 . 4608367 . 10.1016/S0140-6736(14)61730-X .
  14. Web site: SORT1 - Sortilin precursor - Homo sapiens (Human) - SORT1 gene & protein. www.uniprot.org. 2016-08-16.
  15. Quistgaard EM, Madsen P, Grøftehauge MK, Nissen P, Petersen CM, Thirup SS . Ligands bind to Sortilin in the tunnel of a ten-bladed beta-propeller domain . Nature Structural & Molecular Biology . 16 . 1 . 96–98 . January 2009 . 19122660 . 10.1038/nsmb.1543 . 205522786 .
  16. Nykjaer A, Willnow TE . Sortilin: a receptor to regulate neuronal viability and function . Trends in Neurosciences . 35 . 4 . 261–270 . April 2012 . 22341525 . 10.1016/j.tins.2012.01.003 . 28152980 .
  17. Quistgaard EM, Grøftehauge MK, Madsen P, Pallesen LT, Christensen B, Sørensen ES, Nissen P, Petersen CM, Thirup SS . 6 . Revisiting the structure of the Vps10 domain of human sortilin and its interaction with neurotensin . Protein Science . 23 . 9 . 1291–1300 . September 2014 . 24985322 . 4243999 . 10.1002/pro.2512 .
  18. Leloup N, Lössl P, Meijer DH, Brennich M, Heck AJ, Thies-Weesie DM, Janssen BJ . Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release . Nature Communications . 8 . 1 . 1708 . November 2017 . 29167428 . 5700061 . 10.1038/s41467-017-01485-5 . 2017NatCo...8.1708L .
  19. Schmidt V, Willnow TE . Protein sorting gone wrong--VPS10P domain receptors in cardiovascular and metabolic diseases . Atherosclerosis . 245 . 194–199 . February 2016 . 26724530 . 10.1016/j.atherosclerosis.2015.11.027 . free .
  20. Akil H, Perraud A, Mélin C, Jauberteau MO, Mathonnet M . Fine-tuning roles of endogenous brain-derived neurotrophic factor, TrkB and sortilin in colorectal cancer cell survival . PLOS ONE . 6 . 9 . e25097 . 2011-01-01 . 21966426 . 3180371 . 10.1371/journal.pone.0025097 . free . 2011PLoSO...625097A .
  21. Su X, Chen L, Chen X, Dai C, Wang B . Emerging roles of sortilin in affecting the metabolism of glucose and lipid profiles . Bosnian Journal of Basic Medical Sciences . 22 . 3 . 340–352 . June 2022 . 34784266 . 9162750 . 10.17305/bjbms.2021.6601 .
  22. Nielsen MS, Jacobsen C, Olivecrona G, Gliemann J, Petersen CM . Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase . The Journal of Biological Chemistry . 274 . 13 . 8832–8836 . March 1999 . 10085125 . 10.1074/jbc.274.13.8832 . free .
  23. Ariga M, Nedachi T, Katagiri H, Kanzaki M . Functional role of sortilin in myogenesis and development of insulin-responsive glucose transport system in C2C12 myocytes . The Journal of Biological Chemistry . 283 . 15 . 10208–10220 . April 2008 . 18258592 . 10.1074/jbc.M710604200 . free .
  24. Maeda S, Nobukuni T, Shimo-Onoda K, Hayashi K, Yone K, Komiya S, Inoue I . Sortilin is upregulated during osteoblastic differentiation of mesenchymal stem cells and promotes extracellular matrix mineralization . Journal of Cellular Physiology . 193 . 1 . 73–79 . October 2002 . 12209882 . 10.1002/jcp.10151 . 32754981 .
  25. Strong A, Rader DJ . Sortilin as a regulator of lipoprotein metabolism . Current Atherosclerosis Reports . 14 . 3 . 211–218 . June 2012 . 22538429 . 7089359 . 10.1007/s11883-012-0248-x .
  26. Zhong LY, Cayabyab FS, Tang CK, Zheng XL, Peng TH, Lv YC . Sortilin: A novel regulator in lipid metabolism and atherogenesis . Clinica Chimica Acta; International Journal of Clinical Chemistry . 460 . 11–17 . September 2016 . 27312323 . 10.1016/j.cca.2016.06.013 .
  27. Kjolby M, Andersen OM, Breiderhoff T, Fjorback AW, Pedersen KM, Madsen P, Jansen P, Heeren J, Willnow TE, Nykjaer A . 6 . Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export . Cell Metabolism . 12 . 3 . 213–223 . September 2010 . 20816088 . 10.1016/j.cmet.2010.08.006 . free .
  28. Carlo AS . Sortilin, a novel APOE receptor implicated in Alzheimer disease . Prion . 7 . 5 . 378–382 . 2013-10-01 . 24121631 . 4134342 . 10.4161/pri.26746 .
  29. Jin C, Liu X, Zhang F, Wu Y, Yuan J, Zhu J, Zhang F, Wang G, Cheng Z . 6 . An updated meta-analysis of the association between SORL1 variants and the risk for sporadic Alzheimer's disease . Journal of Alzheimer's Disease . 37 . 2 . 429–437 . 2013-01-01 . 23948893 . 10.3233/JAD-130533 .
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  31. Andersson CH, Hansson O, Minthon L, Andreasen N, Blennow K, Zetterberg H, Skoog I, Wallin A, Nilsson S, Kettunen P . 6 . A Genetic Variant of the Sortilin 1 Gene is Associated with Reduced Risk of Alzheimer's Disease . Journal of Alzheimer's Disease . 53 . 4 . 1353–1363 . July 2016 . 27392867 . 5147507 . 10.3233/JAD-160319 .
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