View source for 6iyc


==Recognition of the Amyloid Precursor Protein by Human gamma-secretase==
<SX load='6iyc' size='340' side='right' viewer='molstar' caption='[[6iyc]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6iyc]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IYC OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6IYC FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PC1:1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>PC1</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NCSTN, KIAA0253, UNQ1874/PRO4317 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), PSEN1, AD3, PS1, PSNL1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), APH1A, PSF, CGI-78, UNQ579/PRO1141 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), PSENEN, PEN2, MDS033 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), APP, A4, AD1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6iyc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6iyc OCA], [http://pdbe.org/6iyc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6iyc RCSB], [http://www.ebi.ac.uk/pdbsum/6iyc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6iyc ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/PEN2_HUMAN PEN2_HUMAN]] Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. [[http://www.uniprot.org/uniprot/NICA_HUMAN NICA_HUMAN]] Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. [[http://www.uniprot.org/uniprot/PSN1_HUMAN PSN1_HUMAN]] Defects in PSEN1 are a cause of Alzheimer disease type 3 (AD3) [MIM:[http://omim.org/entry/607822 607822]]. AD3 is a familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death.<ref>PMID:12058025</ref> <ref>PMID:7596406</ref> <ref>PMID:8634711</ref> <ref>PMID:8634712</ref> <ref>PMID:7651536</ref> <ref>PMID:7550356</ref> <ref>PMID:8733303</ref> <ref>PMID:9225696</ref> <ref>PMID:9298817</ref> <ref>PMID:9172170</ref> <ref>PMID:9833068</ref> <ref>PMID:9384602</ref> <ref>PMID:9521423</ref> <ref>PMID:10200054</ref> <ref>PMID:9719376</ref> <ref>PMID:9507958</ref> <ref>PMID:9831473</ref> <ref>PMID:10441572</ref> <ref>PMID:10090481</ref> <ref>PMID:10447269</ref> <ref>PMID:10533070</ref> <ref>PMID:10025789</ref> <ref>PMID:10208579</ref> <ref>PMID:10439444</ref> <ref>PMID:10631141</ref> <ref>PMID:10644793</ref> <ref>PMID:11027672</ref> [:]<ref>PMID:11710891</ref> <ref>PMID:11920851</ref> <ref>PMID:12048239</ref> <ref>PMID:12484344</ref> <ref>PMID:12493737</ref>   Defects in PSEN1 are a cause of frontotemporal dementia (FTD) [MIM:[http://omim.org/entry/600274 600274]].  Defects in PSEN1 are the cause of cardiomyopathy dilated type 1U (CMD1U) [MIM:[http://omim.org/entry/613694 613694]]. It is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.<ref>PMID:17186461</ref>   Defects in PSEN1 are the cause of familial acne inversa type 3 (ACNINV3) [MIM:[http://omim.org/entry/613737 613737]]. A chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty.<ref>PMID:20929727</ref>  [[http://www.uniprot.org/uniprot/A4_HUMAN A4_HUMAN]] Defects in APP are the cause of Alzheimer disease type 1 (AD1) [MIM:[http://omim.org/entry/104300 104300]]. AD1 is a familial early-onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death.<ref>PMID:8476439</ref> <ref>PMID:15201367</ref> <ref>PMID:1671712</ref> <ref>PMID:1908231</ref> <ref>PMID:1678058</ref> <ref>PMID:1944558</ref> <ref>PMID:1925564</ref> <ref>PMID:1415269</ref> <ref>PMID:1303239</ref> <ref>PMID:1302033</ref> <ref>PMID:1303275</ref> <ref>PMID:8267572</ref> <ref>PMID:8290042</ref> <ref>PMID:8577393</ref> <ref>PMID:9328472</ref> <ref>PMID:9754958</ref> <ref>PMID:10097173</ref> <ref>PMID:10631141</ref> <ref>PMID:10665499</ref> <ref>PMID:10867787</ref> <ref>PMID:11063718</ref> <ref>PMID:11311152</ref> <ref>PMID:11528419</ref> <ref>PMID:12034808</ref> <ref>PMID:15365148</ref> <ref>PMID:15668448</ref>   Defects in APP are the cause of cerebral amyloid angiopathy APP-related (CAA-APP) [MIM:[http://omim.org/entry/605714 605714]]. A hereditary localized amyloidosis due to amyloid-beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque-like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications.<ref>PMID:10821838</ref> <ref>PMID:2111584</ref> <ref>PMID:11409420</ref> <ref>PMID:12654973</ref> <ref>PMID:16178030</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/PEN2_HUMAN PEN2_HUMAN]] Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Probably represents the last step of maturation of gamma-secretase, facilitating endoproteolysis of presenilin and conferring gamma-secretase activity.<ref>PMID:12522139</ref> <ref>PMID:12763021</ref>  [[http://www.uniprot.org/uniprot/NICA_HUMAN NICA_HUMAN]] Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor required for the assembly of the gamma-secretase complex. [[http://www.uniprot.org/uniprot/APH1A_HUMAN APH1A_HUMAN]] Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor for the presenilin homodimer that promotes the formation of a stable complex.<ref>PMID:12297508</ref> <ref>PMID:12522139</ref> <ref>PMID:12763021</ref>  [[http://www.uniprot.org/uniprot/PSN1_HUMAN PSN1_HUMAN]] Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. Stimulates cell-cell adhesion though its association with the E-cadherin/catenin complex. Under conditions of apoptosis or calcium influx, cleaves E-cadherin promoting the disassembly of the E-cadherin/catenin complex and increasing the pool of cytoplasmic beta-catenin, thus negatively regulating Wnt signaling. May also play a role in hematopoiesis.<ref>PMID:10545183</ref> <ref>PMID:10593990</ref> <ref>PMID:10206644</ref> <ref>PMID:10899933</ref> <ref>PMID:10811883</ref> <ref>PMID:11226248</ref> <ref>PMID:15341515</ref> <ref>PMID:16305624</ref>  [[http://www.uniprot.org/uniprot/A4_HUMAN A4_HUMAN]] Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>   Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with Also bind GPC1 in lipid rafts.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>   Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain (By similarity).<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>   The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>   N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Cleavage of amyloid precursor protein (APP) by the intramembrane protease gamma-secretase is linked to Alzheimer's disease (AD). We report an atomic structure of human gamma-secretase in complex with a transmembrane (TM) APP fragment at 2.6-angstrom resolution. The TM helix of APP closely interacts with five surrounding TMs of PS1 (the catalytic subunit of gamma-secretase). A hybrid beta sheet, which is formed by a beta strand from APP and two beta strands from PS1, guides gamma-secretase to the scissile peptide bond of APP between its TM and beta strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from AD patients. This structure, together with that of gamma-secretase bound to Notch, reveal contrasting features of substrate binding, which may be applied toward the design of substrate-specific inhibitors.

Recognition of the amyloid precursor protein by human gamma-secretase.,Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y Science. 2019 Feb 15;363(6428). pii: science.aaw0930. doi:, 10.1126/science.aaw0930. Epub 2019 Jan 10. PMID:30630874<ref>PMID:30630874</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6iyc" style="background-color:#fffaf0;"></div>

==See Also==
*[[Gamma secretase complex|Gamma secretase complex]]
== References ==
<references/>
__TOC__
</SX>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Guo, X]]
[[Category: Lei, J]]
[[Category: Shi, Y]]
[[Category: Yang, G]]
[[Category: Zhou, Q]]
[[Category: Zhou, R]]
[[Category: Complex]]
[[Category: Membrane protein]]