SorCS2

Last updated
SORCS2
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SORCS2 , sortilin related VPS10 domain containing receptor 2
External IDs OMIM: 606284; MGI: 1932289; HomoloGene: 56899; GeneCards: SORCS2; OMA:SORCS2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

57537

81840

Ensembl

ENSG00000184985

ENSMUSG00000029093

UniProt

Q96PQ0

Q9EPR5

RefSeq (mRNA)

NM_020777

NM_030889

RefSeq (protein)

NP_065828

NP_112151

Location (UCSC) Chr 4: 7.19 – 7.74 Mb Chr 5: 36.17 – 36.56 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The SorCS2 (sortilin-related Vps10p domain containing receptor 2) 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.... [5]

Contents

SorCS2 is a member of the mammalian Vps10p (vacuolar protein sorting 10 protein) domain family consisting of five transmembrane proteins with structural similarities: SorCS1, SorCS2, SorCS3, SorLA (sorting protein-related receptor with A-type repeats), and sortilin. [6] SorCS2 specifically has critical roles in neuronal viability and function. Single nucleotide polymorphisms (SNPs) in the protein has been associated with a range of diseases including attention-deficit hyperactivity disorder (ADHD), [7] bipolar disorders, [8] and schizophrenia, [9] and the receptor family has also been associated with Alzheimer's disease [10] and type 2 diabetes. [11]

Discovery

The Vps10p domain receptor family was based on the discovery of SorLA in 1996 [12] and sortilin in 1997, [13] and has since been expanded with the SorCS subfamily with SorCS2 being described in 2001 [14] [15]

SorCS2 was first found from isolated cDNA in murine floor plate samples of the central nervous system (CNS) as well as in regions of the brain. The cDNA contained the characteristic Vps10p domain enabling its classification as a SorCS protein. [14] Not long after, a corresponding partial cDNA was found in human samples, and it was possible to determine the missing N-terminal by homology to murine SorCS2. [15]

Structure

SorCS2 is composed of a small intracellular region making a single pass into the extracellular environment where the large Vps10p domain make up a beta-propeller structure consisting of 10 propeller blade-like beta sheet regions. The Vps10p domain contains at least 2 unspecific ligand binding sites. [6] The domain also contains a furin cleavage site. [16] The extracellular region of SorCS proteins also include a LR (leucine rich domain) containing imperfect LR repeats (LRRs) which are known to serve as interaction and adhesion domains [15]

Modifications in Vps10p-type receptors include glycosylations. [17] and they also contain a propeptide which is proteolytically cleaved off to make them active [6]

In the non-neuronal glia cells, SorCS2 is cleaved and a linkage forms a two-chained product distinct from that in neurons which is a single chained. The processing in glia cells have been linked to proapoptotic properties not found in neuronal SorCS2. [18] This differential processing is thought to be common in Vps10p domain proteins where it regulates receptor functionality [6]

Dimerization

Efforts have been made to elucidate the structure of SorCS2, and this has allowed determination of dimerization of SorCS2 and the other two SorCS proteins with only few monomeric structures found. This dimerization is promoted by deglycosylation at least in SorCS1. [6] Structurally, the Vps10p domains in SorCS proteins can be found next to each other, but uniquely for SorCS2 it is prevalently found in a dimer where the domains are located away from each other and connected at a two-fold rotation axis for the dimer. [6] The different types of dimers could explain correspondingly different functions of SorCS2 found in different tissues. In addition to the homodimers described, the SorCS proteins also forms heterodimers within this subfamily. [6] Crystal structures of the full extracellular portion of SorCS2 have uncovered that SorCS2 consists of six domains. [19] Five domains contribute to the dimerization of SorCS2. Despite the extensive dimerization interface, SorCS2 has substantial conformational plasticity. [19]

Localization

SorCS2 and related proteins in the Vps10p domain family are predominantly found in neurons in the brain, but are also present in other tissues. [20] In terms of brain localization SorCS2 has been found predominantly in thalamus, floor plate of the midbrain and spinal cord, ventricular zones of hippocampal and accumbens areas, meninges, and Schwann cells. The localization is distinct from the other Vps10p receptor sortilin [21]

SorCS2 has further been found in tissues that are not brain related in smaller amounts e.g. in structures of mesodermal origin such as adipose tissue, striated muscle tissues, and developing bone as well as connective tissue such as the dermis, submucosal, and submesothelial tissues in the gut, and the bronchial system. Although the presence in these tissues are largely uninvestigated, they still form the basis for further specific functions in non-brain tissue. [20]

Function

All members of the Vps10p protein family are multiligand receptors. [22] [23] They can take part in cellular trafficking and signaling through ligand binding in response to cellular conditions. [24] [25] [26] Examples of ligands are neurotrophic factors, amyloid precursor protein (APP), lipoproteins, and cytokines. [27] In addition to depending on the cellular context, the affinity for specific ligands can also be modulated by the monomer/dimer ratio. [6]

BDNF-dependent plasticity

Hippocampal N-methyl-D-aspartate (NMDA) receptor-dependent synaptic plasticity is found to be deficient at least in SorCS2 mutant mice, strongly suggesting a link between the two. SorCS2 deficient mice also show decreased long-term memory, higher tendency to take risks, and to have a more stimuli seeking behaviour than corresponding SorCS2 normal mice. [26]

The decrease in plasticity is attributed to the fact that SorCS2 forms a complex with p75NTR, a neurotrophin receptor which interacts with proBDNF (brain-derived neurotrophic factor) and TrkB (BDNF receptor tyrosine kinase) inside neurons in the hippocampal region of the brain to modulate synapse depression and potentiation respectively. Thus, SorCS2 could be the link between BDNF/proBDNF signaling and mental disorders. Deficiency in this signaling can affect the strengthening and weakening of synapses, that is, neuronal plasticity. [26]

Clinical significance

Alcohol withdrawal

When trying to stop excessive alcohol consumption alcohol withdrawal (AW) is physiological responses that in some cases can cause life-threatening seizures. SorCS2 has been associated with the severity of AW in genome analysis of European American test subjects, although no such connection could be made in African American samples [28]

A specific SorCS2 risk haplotype disrupts a transcription factor (TF) binding site in a stress hormone-modulated regulatory enhancer element with activity in human hippocampus. This region of the brain is already known for its association with AW. This increases the severity of AW in patients with alcoholism. Exposure to ethanol and glucocorticoids have been found to act as up-regulators of SorCS2, causing worsening of the problems if the risk variant of SorCS2 is present. [28]

See also

Related Research Articles

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References

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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  7. ↑ Alemany, Silvia; Ribasés, Marta; Vilor-Tejedor, Natàlia; Bustamante, Mariona; Sánchez-Mora, Cristina; Bosch, Rosa; Richarte, Vanesa; Cormand, Bru; Casas, Miguel (2015-07-14). "New suggestive genetic loci and biological pathways for attention function in adult attention-deficit/hyperactivity disorder". American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 168 (6): 459–470. doi: 10.1002/ajmg.b.32341 . ISSN   1552-4841. PMID   26174813. S2CID   38488226.
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  11. ↑ Goodarzi, Mark O.; Lehman, Donna M.; Taylor, Kent D.; Guo, Xiuqing; Cui, Jinrui; Quiñones, Manuel J.; Clee, Susanne M.; Yandell, Brian S.; Blangero, John (2007-07-01). "SORCS1: A Novel Human Type 2 Diabetes Susceptibility Gene Suggested by the Mouse". Diabetes. 56 (7): 1922–1929. doi: 10.2337/db06-1677 . ISSN   0012-1797. PMID   17426289.
  12. ↑ Jacobsen, L.; Madsen, P.; Moestrup, S. K.; Lund, A. H.; Tommerup, N.; Nykjaer, A.; Sottrup-Jensen, L.; Gliemann, J.; Petersen, C. M. (1996-12-06). "Molecular characterization of a novel human hybrid-type receptor that binds the alpha2-macroglobulin receptor-associated protein". The Journal of Biological Chemistry. 271 (49): 31379–31383. doi: 10.1074/jbc.271.49.31379 . ISSN   0021-9258. PMID   8940146.
  13. ↑ Petersen, C. M.; Nielsen, M. S.; Nykjaer, A.; Jacobsen, L.; Tommerup, N.; Rasmussen, H. H.; Roigaard, H.; Gliemann, J.; Madsen, P. (1997-02-07). "Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography". The Journal of Biological Chemistry. 272 (6): 3599–3605. doi: 10.1074/jbc.272.6.3599 . ISSN   0021-9258. PMID   9013611.
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  16. ↑ Hosaka, M.; Nagahama, M.; Kim, W. S.; Watanabe, T.; Hatsuzawa, K.; Ikemizu, J.; Murakami, K.; Nakayama, K. (1991-07-05). "Arg-X-Lys/Arg-Arg motif as a signal for precursor cleavage catalyzed by furin within the constitutive secretory pathway". The Journal of Biological Chemistry. 266 (19): 12127–12130. doi: 10.1016/S0021-9258(18)98867-8 . ISSN   0021-9258. PMID   1905715.
  17. ↑ Hermey, Guido; Riedel, I.Björn; Hampe, Wolfgang; Schaller, H.Chica; Hermans-Borgmeyer, Irm (1999-12-20). "Identification and Characterization of SorCS, a Third Member of a Novel Receptor Family". Biochemical and Biophysical Research Communications. 266 (2): 347–351. doi:10.1006/bbrc.1999.1822. ISSN   0006-291X. PMID   10600506.
  18. ↑ Glerup, Simon; Olsen, Ditte; Vaegter, Christian B.; Gustafsen, Camilla; Sjoegaard, Susanne S.; Hermey, Guido; Kjolby, Mads; Molgaard, Simon; Ulrichsen, Maj (June 2014). "SorCS2 Regulates Dopaminergic Wiring and Is Processed into an Apoptotic Two-Chain Receptor in Peripheral Glia". Neuron. 82 (5): 1074–1087. doi: 10.1016/j.neuron.2014.04.022 . hdl: 11858/00-001M-0000-0027-792B-3 . ISSN   0896-6273. PMID   24908487.
  19. 1 2 Leloup, Nadia; Chataigner, Lucas M. P.; Janssen, Bert J. C. (2018-07-30). "Structural insights into SorCS2–Nerve Growth Factor complex formation". Nature Communications. 9 (1): 2979. Bibcode:2018NatCo...9.2979L. doi:10.1038/s41467-018-05405-z. ISSN   2041-1723. PMC   6065357 . PMID   30061605.
  20. 1 2 Boggild, Simon; Molgaard, Simon; Glerup, Simon; Nyengaard, Jens Randel (2016-03-10). "Spatiotemporal patterns of sortilin and SorCS2 localization during organ development". BMC Cell Biology. 17 (1): 8. doi: 10.1186/s12860-016-0085-9 . ISSN   1471-2121. PMC   4785631 . PMID   26964886.
  21. ↑ Boggild, Simon; Molgaard, Simon; Glerup, Simon; Nyengaard, Jens Randel (2018-02-20). "Highly segregated localization of the functionally related vps10p receptors sortilin and SorCS2 during neurodevelopment". Journal of Comparative Neurology. 526 (8): 1267–1286. doi:10.1002/cne.24403. ISSN   0021-9967. PMID   29405286. S2CID   46869016.
  22. ↑ Willnow, Thomas E.; Petersen, Claus M.; Nykjaer, Anders (2008-11-12). "VPS10P-domain receptors — regulators of neuronal viability and function". Nature Reviews Neuroscience. 9 (12): 899–909. doi:10.1038/nrn2516. ISSN   1471-003X. PMID   19002190. S2CID   25776764.
  23. ↑ Willnow, Thomas E; Kjølby, Mads; Nykjaer, Anders (April 2011). "Sortilins: new players in lipoprotein metabolism". Current Opinion in Lipidology. 22 (2): 79–85. doi:10.1097/mol.0b013e3283416f2b. ISSN   0957-9672. PMID   21124217. S2CID   205829395.
  24. ↑ Nykjaer, Anders; Lee, Ramee; Teng, Kenneth K.; Jansen, Pernille; Madsen, Peder; Nielsen, Morten S.; Jacobsen, Christian; Kliemannel, Marco; Schwarz, Elisabeth (2004-02-26). "Sortilin is essential for proNGF-induced neuronal cell death". Nature. 427 (6977): 843–848. Bibcode:2004Natur.427..843N. doi:10.1038/nature02319. ISSN   0028-0836. PMID   14985763. S2CID   4343450.
  25. ↑ Larsen, Jakob Vejby; Hansen, Maria; Møller, Bjarne; Madsen, Peder; Scheller, Jürgen; Nielsen, Morten; Petersen, Claus Munck (2010-09-01). "Sortilin Facilitates Signaling of Ciliary Neurotrophic Factor and Related Helical Type 1 Cytokines Targeting the gp130/Leukemia Inhibitory Factor Receptor β Heterodimer". Molecular and Cellular Biology. 30 (17): 4175–4187. doi:10.1128/MCB.00274-10. ISSN   0270-7306. PMC   2937557 . PMID   20584990.
  26. 1 2 3 Glerup, S; Bolcho, U; Mølgaard, S; Bøggild, S; Vaegter, C B; Smith, A H; Nieto-Gonzalez, J L; Ovesen, P L; Pedersen, L F (2016-07-26). "SorCS2 is required for BDNF-dependent plasticity in the hippocampus". Molecular Psychiatry. 21 (12): 1740–1751. doi: 10.1038/mp.2016.108 . ISSN   1359-4184. PMID   27457814. S2CID   21763820.
  27. ↑ Glerup, S.; Nykjaer, A.; Vaegter, C. B. (2014), "Sortilins in Neurotrophic Factor Signaling", Neurotrophic Factors, Handbook of Experimental Pharmacology, vol. 220, Springer Berlin Heidelberg, pp. 165–189, doi:10.1007/978-3-642-45106-5_7, ISBN   9783642451058, PMID   24668473
  28. 1 2 Smith, Andrew H.; Ovesen, Peter L.; Skeldal, Sune; Yeo, Seungeun; Jensen, Kevin P.; Olsen, Ditte; Diazgranados, Nancy; Zhao, Hongyu; Farrer, Lindsay A. (2018-10-25). "Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2". Alcoholism: Clinical and Experimental Research. 42 (12): 2337–2348. doi:10.1111/acer.13890. ISSN   0145-6008. PMC   6317871 . PMID   30252935.
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