Biology:APLP2

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Amyloid-like protein 2, also known as APLP2, is a protein that in humans is encoded by the APLP2 gene.[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

  1. ↑ 1.0 1.1 "Entrez Gene: APLP2 Amyloid beta (A4) precursor-like protein 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=334. 
  2. ↑ "Assignment of amyloid-precursor-like protein 2 gene (APLP2) to 11q24 by fluorescent in situ hybridization". Cytogenetics and Cell Genetics 87 (3–4): 215–6. 1999. doi:10.1159/000015472. PMID 10702673. 
  3. ↑ 3.0 3.1 "Identification of the Alzheimer's disease amyloid precursor protein (APP) and its homologue APLP2 as essential modulators of glucose and insulin homeostasis and growth". The Journal of Pathology 215 (2): 155–63. June 2008. doi:10.1002/path.2343. PMID 18393365. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "APLP2 - Amyloid-like protein 2 precursor - Homo sapiens (Human) - APLP2 gene & protein". https://www.uniprot.org/uniprot/Q06481. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 "The amyloid precursor protein and its homologues: structural and functional aspects of native and pathogenic oligomerization". European Journal of Cell Biology 91 (4): 234–9. April 2012. doi:10.1016/j.ejcb.2011.01.017. PMID 21459473. 
  6. ↑ "Expression, purification and characterization of a Kunitz-type protease inhibitor domain from human amyloid precursor protein homolog". FEBS Letters 338 (1): 53–7. January 1994. doi:10.1016/0014-5793(94)80115-0. PMID 8307156. 
  7. ↑ "Specificity of amyloid precursor-like protein 2 interactions with MHC class I molecules". Immunogenetics 60 (6): 303–13. June 2008. doi:10.1007/s00251-008-0296-0. PMID 18452037. 
  8. ↑ "Amyloid precursor-like protein 2 increases the endocytosis, instability, and turnover of the H2-K(d) MHC class I molecule". Journal of Immunology 181 (3): 1978–87. August 2008. doi:10.4049/jimmunol.181.3.1978. PMID 18641335. PMC 2607064. http://www.jimmunol.org/cgi/content/abstract/181/3/1978. 
  9. ↑ "APLP2 regulates neuronal stem cell differentiation during cortical development". Journal of Cell Science 126 (Pt 5): 1268–77. March 2013. doi:10.1242/jcs.122440. PMID 23345401. 
  10. ↑ 10.0 10.1 10.2 "The APP family of proteins: similarities and differences". Biochemical Society Transactions 35 (Pt 2): 416–20. April 2007. doi:10.1042/BST0350416. PMID 17371289. 
  11. ↑ "Embryonic stem cell-derived neurons as a cellular system to study gene function: lack of amyloid precursor proteins APP and APLP2 leads to defective synaptic transmission". Stem Cells 26 (8): 2153–63. August 2008. doi:10.1634/stemcells.2008-0010. PMID 18535156. 
  12. ↑ "Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis". The Journal of Neuroscience 29 (35): 10788–801. September 2009. doi:10.1523/JNEUROSCI.2132-09.2009. PMID 19726636. 
  13. ↑ "APP on the move". Trends in Molecular Medicine 8 (4): 152–5. 2002. doi:10.1016/S1471-4914(02)02320-1. PMID 11927267. 
  14. ↑ "The role of APP and APLP for synaptic transmission, plasticity, and network function: lessons from genetic mouse models". Experimental Brain Research 217 (3–4): 435–40. April 2012. doi:10.1007/s00221-011-2894-6. PMID 22006270. 
  15. ↑ 15.0 15.1 "Deletion of the amyloid precursor-like protein 2 (APLP2) does not affect hippocampal neuron morphology or function". Molecular and Cellular Neurosciences 49 (4): 448–55. April 2012. doi:10.1016/j.mcn.2012.02.001. PMID 22353605. 
  16. ↑ "The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics". Science 297 (5580): 353–6. July 2002. doi:10.1126/science.1072994. PMID 12130773. Bibcode: 2002Sci...297..353H. 
  17. ↑ "Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein". Proceedings of the National Academy of Sciences of the United States of America 93 (20): 10832–7. October 1996. doi:10.1073/pnas.93.20.10832. PMID 8855266. Bibcode: 1996PNAS...9310832G. 
  18. ↑ "Molecular cloning of human Fe65L2 and its interaction with the Alzheimer's beta-amyloid precursor protein". Neuroscience Letters 261 (3): 143–6. February 1999. doi:10.1016/S0304-3940(98)00995-1. PMID 10081969. 

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