Sortilin 1

Last updated
SORT1
Protein SORT1 PDB 3F6K.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SORT1 , Gp95, LDLCQ6, NT3, NTR3, Sortilin 1
External IDs OMIM: 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 Mb Chr 3: 108.19 – 108.27 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

Contents

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

Related Research Articles

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<span class="mw-page-title-main">LDL receptor</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Low-affinity nerve growth factor receptor</span> Human protein-coding gene

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<span class="mw-page-title-main">Liver X receptor</span> Nuclear receptor

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<span class="mw-page-title-main">SORL1</span> Protein-coding gene in the species Homo sapiens

Sortilin-related receptor, L(DLR class) A repeats containing is a protein that in humans is encoded by the SORL1 gene.

Neurotensin receptors are transmembrane receptors that bind the neurotransmitter neurotensin. Two of the receptors encoded by the NTSR1 and NTSR2 genes contain seven transmembrane helices and are G protein coupled. Numerous crystal structures have been reported for the neurotensin receptor 1 (NTS1). The third receptor has a single transmembrane domain and is encoded by the SORT1 gene.

<span class="mw-page-title-main">LDL-receptor-related protein-associated protein</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">CX3C motif chemokine receptor 1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Peroxisome proliferator-activated receptor alpha</span> Nuclear receptor protein found in humans

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<span class="mw-page-title-main">OLR1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">LRP2</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">GGA1</span> Protein-coding gene in the species Homo sapiens

ADP-ribosylation factor-binding protein GGA1 is a protein that in humans is encoded by the GGA1 gene.

<span class="mw-page-title-main">LRP1</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">PCSK9</span> Mammalian protein found in humans

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<span class="mw-page-title-main">Neurotensin receptor 2</span> Protein-coding gene in the species Homo sapiens

Neurotensin receptor type 2 is a protein that in humans is encoded by the NTSR2 gene.

<span class="mw-page-title-main">Neurotensin receptor 1</span> Protein-coding gene in the species Homo sapiens

Neurotensin receptor type 1 is a protein that in humans is encoded by the NTSR1 gene. For a crystal structure of NTS1, see pdb code 4GRV. In addition, high-resolution crystal structures have been determined in complex with the peptide full agonist NTS8-13, the non-peptide full agonist SRI-9829, the partial agonist RTI-3a, and the antagonists / inverse agonists SR48692 and SR142948A, as well as in the ligand-free apo state., see PDB codes 6YVR (NTSR1-H4X:NTS8–13), 6Z4V (NTSR1-H4bmX:NTS8–13), 6Z8N (NTSR1-H4X:SRI-9829), 6ZA8 (NTSR1-H4X:RTI-3a), 6Z4S (NTSR1-H4bmX:SR48692), 6ZIN (NTSR1-H4X:SR48692), 6Z4Q, and 6Z66.

<span class="mw-page-title-main">GGA2</span> Protein-coding gene in the species Homo sapiens

ADP-ribosylation factor-binding protein GGA2 is a protein that in humans is encoded by the GGA2 gene.

<span class="mw-page-title-main">VPS26A</span> Protein-coding gene in the species Homo sapiens

Vacuolar protein sorting-associated protein 26A is a protein that in humans is encoded by the VPS26A gene.

<span class="mw-page-title-main">SorCS2</span> Gene is found on chromosome 4

The SorCS2 gene is found on chromosome 4 (4p16.1), and is composed of 28 exons. The N-terminal exons which encode the Vps10p domain are spaced by large introns. The functional receptor protein is largely present in the brain. It is 1109 amino acids long, largely neutral, and has a single transmembrane pass....

References

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  33. ↑ Jin C, Liu X, Zhang F, Wu Y, Yuan J, Zhu J, et al. (2013-01-01). "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. doi:10.3233/JAD-130533. PMID   23948893.
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  39. 1 2 Ogawa K, Ueno T, Iwasaki T, Kujiraoka T, Ishihara M, Kunimoto S, et al. (June 2016). "Soluble sortilin is released by activated platelets and its circulating levels are associated with cardiovascular risk factors". Atherosclerosis. 249: 110–115. doi:10.1016/j.atherosclerosis.2016.03.041. PMID   27085161.
  40. 1 2 Jacobsen L, Madsen P, Nielsen MS, Geraerts WP, Gliemann J, Smit AB, Petersen CM (January 2002). "The sorLA cytoplasmic domain interacts with GGA1 and -2 and defines minimum requirements for GGA binding". FEBS Letters. 511 (1–3): 155–158. doi: 10.1016/S0014-5793(01)03299-9 . PMID   11821067. S2CID   21977507.

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