APLP2
Template:Short description Template:Infobox gene Amyloid precursor like protein 2, also known as APLP2, is a protein encoded by the APLP2 gene in humans.[1][2] APLP2 along with APLP1 are important modulators of glucose and insulin homeostasis.[3]
Gene location
The human APLP2 gene is located on the long (q) arm of chromosome 11 at region 2 band 4, from base pair 130, 069, 821 to base pair 130, 144, 811 (GRCh38.p7).[1]
Protein structure
APLP2 consists of 763 amino acids, with 31 amino acids making up the signal peptide and 732 amino acids making up the chain of the protein.[4]
Extracellular domain
The extracellular domain (residues 32-692) contains the E1 domain, E2 domain, and BPTI/Kunitz inhibitor domain.[4][5] The E1 domain contains two independent folding units, the growth factor-like domain (GFLD) and the copper-binding domain (CuBD).[5] GFLD has a highly charged basic surface and a highly flexible region consisting of an N-terminal loop formed by a disulphide bridge.[5] CuBD consists of an alpha-helix that is tightly packed on a triple-stranded beta-sheet.[5]
The E2 domain is the largest subdomain of APLP2 and consists of six alpha-helixes.[5] The N-terminal double stranded coiled coil structure of the first monomer of E2 packs against the C-terminal triple stranded coiled coil structure of the second monomer.[5]
The BPTI/Kunitz inhibitor domain (residues 306-364)[4] is ‘Cys-rich’ and is capable of inhibiting several proteases.[6]
The ectodomain of APLP2 is dimeric and contains multiple binding sites for metal ions and components of the extracellular matrix.[5] These bindings site can bind copper, zinc, collagen and heparan sulfate.[5]
Transmembrane region
The transmembrane region of APLP2 (residues 693-716) is helical in structure.[4]
Cytoplasmic domain
The cytoplasmic domain (resides 717-763)[4] contains a YENPTY sequence suggesting a duel function of the domain.[5] The NPxY motif can function as a signal for endocytosis or the sequence can function to mediate binding of various interactive partners.[5]
Function
APLP2 associates with antigen presentation molecules like MHC class I molecules and regulates their surface expression by enhancing endocytosis.[7][8]
APLP1 and APLP2 double knockout mice display hypoglycemia and hyperinsulinemia indicating that these two proteins are important modulators of glucose and insulin homeostasis.[3] APLP2 has also been shown to regulate development of the brain by regulating migration and differentiation of neural stem cells.[9]
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.[10] 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.[10]
APLP2 plays a role in synaptic plasticity, functioning to promote neurite outgrowth, neural cell migration and copper homeostasis.[10] 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.[11] Moreover, APLP2 together with APP has been demonstrated to exhibit presynaptic and postsynaptic functions in synaptogenesis and maintenance of synapses.[12]
APLP2 has shown to act as a cargo receptor in axonal transport for intact proteins.[13]
Clinical significance
APLP2 is part of a family of mammalian membrane proteins along with APLP1 and amyloid precursor protein (APP).[14] Since APP plays a key role in the molecular pathology of Alzheimer’s disease (AD), it has been hypothesized that APLP2 also plays a role in AD pathogenesis.[15] The amyloid β peptide (Aβ) that is present on APP has been shown to cause neurotoxic effects leading to AD.[16] 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.[15]
Interactions
APLP2 has been shown to interact with APBB1.[17][18]
References
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