{{Short description|Protein-coding gene in the species Homo sapiens}} {{Infobox_gene}} '''Amyloid precursor like protein 2,''' also known as '''APLP2''', is a protein encoded by the ''APLP2'' gene in humans.<ref name="entrez">{{cite web | title = Entrez Gene: APLP2 Amyloid beta (A4) precursor-like protein 2| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=334| access-date = }}</ref><ref name="pmid10702673">{{cite journal | vauthors = Leach R, Ko M, Krawetz SA | title = Assignment of amyloid-precursor-like protein 2 gene (APLP2) to 11q24 by fluorescent in situ hybridization | journal = Cytogenetics and Cell Genetics | volume = 87 | issue = 3–4 | pages = 215–6 | year = 1999 | pmid = 10702673 | doi = 10.1159/000015472 | s2cid = 39798007 }}</ref> APLP2 along with APLP1 are important modulators of glucose and insulin homeostasis.<ref name="pmid18393365"/>
== 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).<ref name="entrez" />
== 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.<ref name="UniProt">{{cite web | url = https://www.uniprot.org/uniprot/Q06481 | title = APLP2 - Amyloid-like protein 2 precursor - Homo sapiens (Human) - APLP2 gene & protein|website=www.uniprot.org|access-date=2016-10-03}}</ref>
=== Extracellular domain ===
The extracellular domain (residues 32-692) contains the E1 domain, E2 domain, and BPTI/Kunitz inhibitor domain.<ref name="UniProt" /><ref name="Kaden_2012">{{cite journal | vauthors = Kaden D, Munter LM, Reif B, Multhaup G | title = The amyloid precursor protein and its homologues: structural and functional aspects of native and pathogenic oligomerization | journal = European Journal of Cell Biology | volume = 91 | issue = 4 | pages = 234–9 | date = April 2012 | pmid = 21459473 | doi = 10.1016/j.ejcb.2011.01.017 }}</ref> The E1 domain contains two independent folding units, the growth factor-like domain (GFLD) and the copper-binding domain (CuBD).<ref name="Kaden_2012" /> GFLD has a highly charged basic surface and a highly flexible region consisting of an N-terminal loop formed by a disulphide bridge.<ref name="Kaden_2012" /> CuBD consists of an alpha-helix that is tightly packed on a triple-stranded beta-sheet.<ref name="Kaden_2012" />
The E2 domain is the largest subdomain of APLP2 and consists of six alpha-helixes.<ref name="Kaden_2012" /> 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.<ref name="Kaden_2012" />
The BPTI/Kunitz inhibitor domain (residues 306-364)<ref name="UniProt" /> is ‘Cys-rich’ and is capable of inhibiting several proteases.<ref>{{cite journal | vauthors = Petersen LC, Bjørn SE, Norris F, Norris K, Sprecher C, Foster DC | title = Expression, purification and characterization of a Kunitz-type protease inhibitor domain from human amyloid precursor protein homolog | journal = FEBS Letters | volume = 338 | issue = 1 | pages = 53–7 | date = January 1994 | pmid = 8307156 | doi=10.1016/0014-5793(94)80115-0| s2cid = 31738626 | doi-access = free | bibcode = 1994FEBSL.338...53P }}</ref>
The ectodomain of APLP2 is dimeric and contains multiple binding sites for metal ions and components of the extracellular matrix.<ref name="Kaden_2012" /> These bindings site can bind copper, zinc, collagen and heparan sulfate.<ref name="Kaden_2012" />
=== Transmembrane region ===
The transmembrane region of APLP2 (residues 693-716) is helical in structure.<ref name="UniProt" />
=== Cytoplasmic domain === The cytoplasmic domain (resides 717-763)<ref name="UniProt" /> contains a YENPTY sequence suggesting a duel function of the domain.<ref name="Kaden_2012" /> The NPxY motif can function as a signal for endocytosis or the sequence can function to mediate binding of various interactive partners.<ref name="Kaden_2012" />
== Function ==
APLP2 associates with antigen presentation molecules like MHC class I molecules and regulates their surface expression by enhancing endocytosis.<ref name="pmid18452037">{{cite journal | vauthors = Tuli A, Sharma M, Naslavsky N, Caplan S, Solheim JC | title = Specificity of amyloid precursor-like protein 2 interactions with MHC class I molecules | journal = Immunogenetics | volume = 60 | issue = 6 | pages = 303–13 | date = June 2008 | pmid = 18452037 | pmc = 2683759 | doi = 10.1007/s00251-008-0296-0 }}</ref><ref name="pmid18641335">{{cite journal | vauthors = Tuli A, Sharma M, McIlhaney MM, Talmadge JE, Naslavsky N, Caplan S, Solheim JC | title = Amyloid precursor-like protein 2 increases the endocytosis, instability, and turnover of the H2-K(d) MHC class I molecule | journal = Journal of Immunology | volume = 181 | issue = 3 | pages = 1978–87 | date = August 2008 | pmid = 18641335 | pmc = 2607064 | doi = 10.4049/jimmunol.181.3.1978 | url = http://www.jimmunol.org/cgi/content/abstract/181/3/1978 }}</ref>
APLP1 and APLP2 double knockout mice display hypoglycemia and hyperinsulinemia indicating that these two proteins are important modulators of glucose and insulin homeostasis.<ref name="pmid18393365">{{cite journal | vauthors = Needham BE, Wlodek ME, Ciccotosto GD, Fam BC, Masters CL, Proietto J, Andrikopoulos S, Cappai R | title = Identification of the Alzheimer's disease amyloid precursor protein (APP) and its homologue APLP2 as essential modulators of glucose and insulin homeostasis and growth | journal = The Journal of Pathology | volume = 215 | issue = 2 | pages = 155–63 | date = June 2008 | pmid = 18393365 | doi = 10.1002/path.2343 | s2cid = 1064378 }}</ref> APLP2 has also been shown to regulate development of the brain by regulating migration and differentiation of neural stem cells.<ref name="pmid23345401">{{cite journal | vauthors = Shariati SA, Lau P, Hassan BA, Müller U, Dotti CG, De Strooper B, Gärtner A | title = APLP2 regulates neuronal stem cell differentiation during cortical development | journal = Journal of Cell Science | volume = 126 | issue = Pt 5 | pages = 1268–77 | date = March 2013 | pmid = 23345401 | doi = 10.1242/jcs.122440 | doi-access = free }}</ref>
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.<ref name="Walsh_2007">{{cite journal | vauthors = Walsh DM, Minogue AM, Sala Frigerio C, Fadeeva JV, Wasco W, Selkoe DJ | title = The APP family of proteins: similarities and differences | journal = Biochemical Society Transactions | volume = 35 | issue = Pt 2 | pages = 416–20 | date = April 2007 | pmid = 17371289 | doi = 10.1042/BST0350416 }}</ref> 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.<ref name="Walsh_2007" />
APLP2 plays a role in synaptic plasticity, functioning to promote neurite outgrowth, neural cell migration and copper homeostasis.<ref name="Walsh_2007" /> 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.<ref>{{cite journal | vauthors = Schrenk-Siemens K, Perez-Alcala S, Richter J, Lacroix E, Rahuel J, Korte M, Müller U, Barde YA, Bibel M | title = 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 | journal = Stem Cells | volume = 26 | issue = 8 | pages = 2153–63 | date = August 2008 | pmid = 18535156 | doi = 10.1634/stemcells.2008-0010 | s2cid = 207240922 | doi-access = free }}</ref> Moreover, APLP2 together with APP has been demonstrated to exhibit presynaptic and postsynaptic functions in synaptogenesis and maintenance of synapses.<ref>{{cite journal | vauthors = Wang Z, Wang B, Yang L, Guo Q, Aithmitti N, Songyang Z, Zheng H | title = Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis | journal = The Journal of Neuroscience | volume = 29 | issue = 35 | pages = 10788–801 | date = September 2009 | pmid = 19726636 | doi = 10.1523/JNEUROSCI.2132-09.2009 | pmc=2757256}}</ref>
APLP2 has shown to act as a cargo receptor in axonal transport for intact proteins.<ref name="Müller_2002">{{cite journal | vauthors = Müller U, Kins S | title = APP on the move | journal = Trends in Molecular Medicine | volume = 8 | issue = 4 | pages = 152–5 | year = 2002 | pmid = 11927267 | doi = 10.1016/S1471-4914(02)02320-1 }}</ref>
== Clinical significance ==
APLP2 is part of a family of mammalian membrane proteins along with APLP1 and amyloid precursor protein (APP).<ref>{{cite journal | vauthors = Korte M, Herrmann U, Zhang X, Draguhn A | title = The role of APP and APLP for synaptic transmission, plasticity, and network function: lessons from genetic mouse models | journal = Experimental Brain Research | volume = 217 | issue = 3–4 | pages = 435–40 | date = April 2012 | pmid = 22006270 | doi = 10.1007/s00221-011-2894-6 | s2cid = 11886993 }}</ref> 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.<ref name="Midthune_2012">{{cite journal | vauthors = Midthune B, Tyan SH, Walsh JJ, Sarsoza F, Eggert S, Hof PR, Dickstein DL, Koo EH | title = Deletion of the amyloid precursor-like protein 2 (APLP2) does not affect hippocampal neuron morphology or function | journal = Molecular and Cellular Neurosciences | volume = 49 | issue = 4 | pages = 448–55 | date = April 2012 | pmid = 22353605 | doi = 10.1016/j.mcn.2012.02.001 | pmc=3348437}}</ref> The amyloid β peptide (Aβ) that is present on APP has been shown to cause neurotoxic effects leading to AD.<ref>{{cite journal | vauthors = Hardy J, Selkoe DJ | title = The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics | journal = Science | volume = 297 | issue = 5580 | pages = 353–6 | date = July 2002 | pmid = 12130773 | doi = 10.1126/science.1072994 | bibcode = 2002Sci...297..353H | s2cid = 15150253 }}</ref> 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.<ref name="Midthune_2012" />
== Interactions ==
APLP2 has been shown to interact with APBB1.<ref name="pmid8855266">{{cite journal | vauthors = Guénette SY, Chen J, Jondro PD, Tanzi RE | title = Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 20 | pages = 10832–7 | date = October 1996 | pmid = 8855266 | pmc = 38241 | doi = 10.1073/pnas.93.20.10832 | bibcode = 1996PNAS...9310832G | doi-access = free }}</ref><ref name="pmid10081969">{{cite journal | vauthors = Tanahashi H, Tabira T | title = Molecular cloning of human Fe65L2 and its interaction with the Alzheimer's beta-amyloid precursor protein | journal = Neuroscience Letters | volume = 261 | issue = 3 | pages = 143–6 | date = February 1999 | pmid = 10081969 | doi = 10.1016/S0304-3940(98)00995-1 | s2cid = 54307954 }}</ref>
== References == {{Reflist|33em}}
==External links== * {{UCSC gene info|APLP2}}
Category:Genes on human chromosome 11