The SorCS2 ( sortilin-related Vps10p domain containing receptor 2) gene is found on

chromosome 4 Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 190 million base pairs (the building material of DNA) and represents between 6 and 6.5 percent of the to ...

(4p16.1), and is composed of 28

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

s. The

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

exons which encode the Vps10p domain are spaced by large

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...

s. The functional

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

protein is largely present in the brain. It is 1109

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s long, largely neutral, and has a single

transmembrane A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...

pass.... 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. 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),

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

s, and

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

, and the receptor family has also been associated with

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

and

type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...

Discovery

The Vps10p domain receptor family was based on the discovery of SorLA in 1996 and sortilin in 1997, and has since been expanded with the SorCS subfamily with SorCS2 being described in 2001 SorCS2 was first found from isolated

cDNA In genetics, complementary DNA (cDNA) is DNA that was reverse transcribed (via reverse transcriptase) from an RNA (e.g., messenger RNA or microRNA). cDNA exists in both single-stranded and double-stranded forms and in both natural and engin ...

murine The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...

floor plate A floor is the bottom surface of a room or vehicle. Floors vary from simple dirt in a cave to many layered surfaces made with modern technology. Floors may be stone, wood, bamboo, metal or any other material that can support the expected load ...

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. 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.

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 In structural biology, a beta-propeller (β-propeller) is a type of all-β protein architecture characterized by 4 to 8 highly symmetrical blade-shaped beta sheets arranged toroidally around a central axis. Together the beta-sheets form a funnel- ...

structure consisting of 10 propeller blade-like

beta sheet The beta sheet (β-sheet, also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gene ...

regions. The Vps10p domain contains at least 2 unspecific

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

binding sites. The domain also contains a furin cleavage site. 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 Modifications in Vps10p-type receptors include

glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

s. and they also contain a

propeptide A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein (or peptide) that can be turned into an active form by post-translational modification, such as breaking off a piece of the molecule or adding on another molecule ...

which is proteolytically cleaved off to make them active In the non-neuronal

glia Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce electrical impulses. The neuroglia make up ...

cells, SorCS2 is cleaved and a linkage forms a two-chained product distinct from that in

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s which is a single chained. The processing in glia cells have been linked to

proapoptotic Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These c ...

properties not found in neuronal SorCS2. This differential processing is thought to be common in Vps10p domain proteins where it regulates receptor functionality

Dimerization

Efforts have been made to elucidate the structure of SorCS2, and this has allowed determination of

dimerization In chemistry, dimerization is the process of joining two identical or similar molecular entities by bonds. The resulting bonds can be either strong or weak. Many symmetrical chemical species are described as dimers, even when the monomer is u ...

of SorCS2 and the other two SorCS proteins with only few

monomer A monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or two- or three-dimensional network in a process called polymerization. Classification Chemis ...

ic structures found. This dimerization is promoted by deglycosylation at least in SorCS1. 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. 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. Crystal structures of the full extracellular portion of SorCS2 have uncovered that SorCS2 consists of six domains. Five domains contribute to the dimerization of SorCS2. Despite the extensive dimerization interface, SorCS2 has substantial conformational plasticity.

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. In terms of brain localization SorCS2 has been found predominantly in

thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...

, floor plate of the

midbrain The midbrain or mesencephalon is the uppermost portion of the brainstem connecting the diencephalon and cerebrum with the pons. It consists of the cerebral peduncles, tegmentum, and tectum. It is functionally associated with vision, hearing, mo ...

and

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...

ventricular zone In vertebrates, the ventricular zone (VZ) is a transient embryonic layer of tissue containing neural stem cells, principally radial glial cells, of the central nervous system (CNS). The VZ is so named because it lines the ventricular system, whi ...

s of

hippocampal The hippocampus (: hippocampi; via Latin from Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the subiculum ar ...

and accumbens areas,

meninges In anatomy, the meninges (; meninx ; ) are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in the subarachnoid spac ...

, and

Schwann cell Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include Satellite glial cell, satellite ...

s. The localization is distinct from the other Vps10p receptor sortilin SorCS2 has further been found in tissues that are not brain related in smaller amounts e.g. in structures of

mesoderm The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical ...

al origin such as

adipose tissue Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...

striated muscle tissue Striated muscle tissue is a muscle tissue that features repeating functional units called sarcomeres. Under the microscope, sarcomeres are visible along muscle fibers, giving a striated appearance to the tissue. The two types of striated muscle a ...

s, and developing bone as well as

connective tissue Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesod ...

such as the

dermis The dermis or corium is a layer of skin between the epidermis (skin), epidermis (with which it makes up the cutis (anatomy), cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from s ...

submucosa The submucosa (or tela submucosa) is a thin layer of tissue in various organs of the gastrointestinal, respiratory, and genitourinary tracts. It is the layer of dense irregular connective tissue that supports the mucosa (mucous membrane) an ...

l, and submesothelial tissues in the gut, and the

bronchial A bronchus ( ; : bronchi, ) is a passage or airway in the lower respiratory tract that conducts Atmosphere of Earth, air into the lungs. The first or primary bronchi to branch from the trachea at the Carina of trachea, carina are the right main b ...

system. Although the presence in these tissues are largely uninvestigated, they still form the basis for further specific functions in non-brain tissue.

Function

All members of the Vps10p protein family are multiligand receptors. They can take part in cellular trafficking and signaling through ligand binding in response to cellular conditions. Examples of ligands are

neurotrophic factors Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and cell differentiation, differentiation of both developing and mature neurons. Most ...

, amyloid precursor protein (APP),

lipoprotein A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...

s, and

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

s. In addition to depending on the cellular context, the affinity for specific ligands can also be modulated by the monomer/dimer ratio.

BDNF-dependent plasticity

Hippocampal ''N''-methyl-D-aspartate (NMDA) receptor-dependent

synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...

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. The decrease in plasticity is attributed to the fact that SorCS2 forms a complex with p75^NTR, a neurotrophin receptor which interacts with pro BDNF (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

synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

s, that is, neuronal plasticity.

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 A specific SorCS2 risk

haplotype A haplotype (haploid genotype) is a group of alleles in an organism that are inherited together from a single parent. Many organisms contain genetic material (DNA) which is inherited from two parents. Normally these organisms have their DNA orga ...

disrupts a transcription factor (TF) binding site in a stress

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

-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 Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World He ...

. Exposure to

ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

and

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...

s have been found to act as up-regulators of SorCS2, causing worsening of the problems if the risk variant of SorCS2 is present.

References

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