Amyloid-like protein 2, also known as APLP2, is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''APLP2''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. APLP2 along with APLP1 are important modulators of

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

and insulin

homeostasis In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...

Gene location

The human ''APLP2'' gene is located on the long (q) arm of

chromosome 11 Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...

at region 2 band 4, from base pair 130, 069, 821 to base pair 130, 144, 811 (GRCh38.p7).

Protein structure

APLP2 consists of 763

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

s, with 31 amino acids making up the signal peptide and 732 amino acids making up the chain of the protein.

Extracellular domain

The extracellular domain (residues 32-692) contains the E1 domain, E2 domain, and BPTI/Kunitz inhibitor domain. The E1 domain contains two independent folding units, the

growth factor-like domain A growth factor-like domain (GFLD) is a protein domain structurally related to epidermal growth factor, which has a high binding affinity for the epidermal growth factor receptor. As structural domains within larger proteins, GFLD regions commonly ...

(GFLD) and the copper-binding domain (CuBD). GFLD has a highly charged basic surface and a highly flexible region consisting of an N-terminal loop formed by a disulphide bridge. CuBD consists of an alpha-helix that is tightly packed on a triple-stranded

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 ge ...

. The E2 domain is the largest subdomain of APLP2 and consists of six alpha-helixes. The N-terminal double stranded coiled coil structure of the first monomer of E2 packs against the

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

triple stranded coiled coil structure of the second monomer. The BPTI/Kunitz inhibitor domain (residues 306-364) is ‘Cys-rich’ and is capable of inhibiting several

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

s. The

ectodomain An ectodomain is the domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction.A notable ...

of APLP2 is dimeric and contains multiple binding sites for metal ions and components of the extracellular matrix. These bindings site can bind copper, zinc, collagen and heparan sulfate.

Transmembrane region

The transmembrane region of APLP2 (residues 693-716) is

helical Helical may refer to: * Helix, the mathematical concept for the shape * Helical engine, a proposed spacecraft propulsion drive * Helical spring, a coilspring * Helical plc, a British property company, once a maker of steel bar stock * Helicoil A t ...

in structure.

Cytoplasmic domain

The cytoplasmic domain (resides 717-763) contains a YENPTY sequence suggesting a duel function of the domain. The NPxY motif can function as a signal for endocytosis or the sequence can function to mediate binding of various interactive partners.

Function

APLP2 associates with antigen presentation molecules like MHC class I molecules and regulates their surface expression by enhancing endocytosis. APLP1 and APLP2 double knockout mice display

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

and

hyperinsulinemia Hyperinsulinemia is a condition in which there are excess levels of insulin circulating in the blood relative to the level of glucose. While it is often mistaken for diabetes or hyperglycaemia, hyperinsulinemia can result from a variety of metabo ...

indicating that these two proteins are important modulators of glucose and insulin homeostasis. APLP2 has also been shown to regulate development of the brain by regulating migration and differentiation of neural stem cells. Double mice knock outs of APLP2 and its homologues, APP and APLP1 have shown a strong indication that APLP2 has the key physiological role among the family members. APLP2/APP double knock out mice and APLP2/APLP1 double knock out mice each show a lethal phenotype (postnatal day 1), whereas APLP1/APP double knock out mice are apparently normal, demonstrating the importance of the APLP2 protein. APLP2 plays a role in

synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits ...

, functioning to promote neurite outgrowth, neural cell migration and copper homeostasis. Analysing the neurons and networks of APP/APLP2 double knock out mice using stem cell-derived neurons and slice cultures, shows deficient excitatory synaptic transmission in this genotype. Moreover, APLP2 together with APP has been demonstrated to exhibit presynaptic and postsynaptic functions in

synaptogenesis Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenes ...

and maintenance of synapses. APLP2 has shown to act as a cargo receptor in axonal transport for intact proteins.

Clinical significance

APLP2 is part of a family of mammalian

membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...

s along with APLP1 and

amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse format ...

(APP). Since APP plays a key role in the molecular pathology of

Alzheimer’s disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...

(AD), it has been hypothesized that APLP2 also plays a role in AD

pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...

. The amyloid β peptide (Aβ) that is present on APP has been shown to cause

neurotoxic Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...

effects leading to AD. Although the Aβ sequence is not present on APLP2, it has been suggested that APLP2 and APP share a functional redundancy whereby both proteins interplay with one another to exhibit physiological functions to do with synapse formation.

Interactions

APLP2 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with

APBB1 Amyloid beta A4 precursor protein-binding family B member 1 is a protein that in humans is encoded by the ''APBB1'' gene. Function The protein encoded by this gene is a member of the Fe65 protein family. It is an adaptor protein localized in th ...

References

External links

* {{UCSC gene info, APLP2 Genes on human chromosome 11