A4_HUMAN » Amyloid beta A4 protein

A4_HUMAN » Amyloid beta A4 protein
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Topology in Plasma membrane
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A4_HUMAN » Amyloid beta A4 protein » ABPP;APPI;APP; Alzheimer disease amyloid protein;Cerebral vascular amyloid peptide;CVAP; PreA4;Protease nexin-II;PN-II;
Hydrophobic Thickness 38.8 ± 4.4 Å
Tilt Angle 6 ± 7°
ΔGtransfer -25.9 kcal/mol
ΔGfold -19.0 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, Reactome, HMDB
Topology Out
TM Segments 700-725 (693-726)
Pathways

Alzheimer's disease (KEGG)

Hemostasis (Reactome)

Immune System (Reactome)

Serotonergic synapse (KEGG)

Signal Transduction (Reactome)

PDB 1owt (124-189), 2fkl (124-189), 2fma (133-189), 2fk2 (133-189), 2fjz (133-189), 2fk1 (133-189), 4pwq (18-190), 4jfn (23-185), 1mwp (28-123), 3umk (370-575), 3umh (370-575), 3umi (370-575), 1tkn (460-569), 2lp1 (671-770), 1ze9 (672-687), 2bp4 (672-687), 1ze7 (672-687), 1bjb (672-699), 1amb (672-699), 1amc (672-699), 1bjc (672-699), 2lfm (672-711), 2m9s (672-711), 1aml (672-711), 1ba4 (672-711), 2m9r (672-711), 1ba6 (672-711), 1iyt (672-713), 1z0q (672-713), 1hz3 (681-706), 2llm (686-726), 2y29 (687-692), 2y2a (687-692), 2mj1 (688-705), 1qyt (696-706), 1qxc (696-706), 1qwp (696-706), 1qcm (696-706), 2fk3 (A/B...=133-189), 3ktm (A/B...=18-190), 2mvx (A/B...=672-711), 2m4j (A/B...=672-711), 2lmq (A/B...=672-711), 2lnq (A/B...=672-711), 2lmp (A/B...=672-711), 2lmn (A/B...=672-711), 2lmo (A/B...=672-711), 2beg (A/B...=672-713), 2y3j (A/B...=701-706), 2y3k (A/B...=706-713), 3ovj (A/B/C/D=687-692), 3moq (A/B/C/D=689-712), 2y3l (A/B/C/G=706-713), 1aap (A/B=287-344), 2loh (A/B=686-726), 3ow9 (A/B=687-692), 2lz3 (A/B=699-726), 2lz4 (A/B=699-726), 3nyj (A=365-567), 3nyl (A=365-570), 4ojf (A=672-679), 3bkj (A=672-687), 3bae (A=672-699), 4hix (A=672-699), 3dxd (B/D=739-770), 3dxc (B/D=739-770), 3dxe (B/D=739-770), 4nge (B/E=672-711), 1taw (B=287-344), 1zjd (B=289-344), 3ayu (B=586-595), 3jq5 (B=672-679), 3jql (B=687-692), 3jti (B=699-706), 4mdr (B=758-767), 3l81 (B=761-767), 2g47 (C/D=672-711), 2wk3 (C/D=672-713), 1x11 (C/D=754-766), 2otk (C=672-711), 3sv1 (D/E/F=754-767), 1ca0 (D/I=289-342), 3l33 (E/F/G/H=290-341), 3u0t (E/F=701-711), 4m1c (G/H=672-711), 1brc (I=287-342), 3mxc (L=754-762), 3mxy (L=754-762), 3ifp (P/Q/R/S=672-678), 3ifo (P/Q=672-678), 2ipu (P/Q=672-679), 4onf (P=672-678), 3ifl (P=672-678), 4ong (P=672-711), 3ifn (P=672-711), 3gci (P=707-713), 2r0w (Q=672-679)
OPM 1amb, 1ba4, 1qcm, 2lfm, 2llm, 2lnq, 2loh, 2lp1, 2lz3, 2lz4, 2mj1, 2y3j, 2y3k, 2y3l, 3jql, 3ow9
Complexes

A4:A4_HUMAN

Interactions

A4, Complex: Transmembrane homodimer of A4 protein, PDBID: 2LOH

ACSL3, Complex: A4:ACSL3, PubMed

ACSL4, Complex: ACSL4:A4, PubMed

ADA17, Complex: A4:ADA17

AIFM3, Complex: A4:AIFM3

APLP1, Complex: A4:APLP1

APLP2, Complex: A4:APLP2

APRIO, Complex: APRIO.PRIO:A4, PubMed

ARAID, Complex: A4:ARAID, PubMed

AREG, Complex: AREG:A4, PubMed

ARMX3, Complex: ARMX3:A4, PubMed

ASGR1, Complex: ASGR1:A4, PubMed

ASPH, Complex: ASPH:A4, PubMed

ATF6A, Complex: ATF6A:A4, PubMed

B2L13, Complex: B2L13:A4, PubMed

BACE1, Complex: A4:BACE1, PubMed

BACE2, Complex: BACE2:A4, PubMed

BET1L, Complex: BET1L:A4, PubMed

BIK, Complex: BIK:A4, PubMed

BMR1B, Complex: A4:BMR1B, PubMed

CA115, Complex: A4:CA115, PubMed

CASC4, Complex: A4:CASC4, PubMed

CC020, Complex: CC020:A4, PubMed

CC033, Complex: CC033:A4, PubMed

CC045, Complex: CC045:A4, PubMed

CC107, Complex: CC107:A4, PubMed

CG053, Complex: CG053:A4, PubMed

CISD2, Complex: CISD2:A4, PubMed

CLC2B, Complex: A4:CLC2B, PubMed

CLIC3, Complex: A4:CLIC3, PubMed

CLM1, Complex: CLM1:A4, PubMed

CLM7, Complex: A4:CLM7, PubMed

COL12, Complex: A4:COL12, PubMed

COPA1, Complex: COPA1:A4, PubMed

COX41, Complex: COX41:A4, PubMed

COX42, Complex: COX42:A4, PubMed

CP20A, Complex: CP20A:A4, PubMed

CS012, Complex: A4:CS012, PubMed

CS018, Complex: CS018:A4, PubMed

CSTN1, Complex: CSTN1:A4, PubMed

CX6A2, Complex: CX6A2:A4, PubMed

CXL16, Complex: A4:CXL16, PubMed

CYB5B, Complex: CYB5B:A4, PubMed

DJB14, Complex: A4:DJB14, PubMed

DLK2, Complex: A4:DLK2, PubMed

DNJC4, Complex: DNJC4:A4, PubMed

DPCR1, Complex: DPCR1:A4, PubMed

DRS7B, Complex: DRS7B:A4, PubMed

EFRD1, Complex: A4:EFRD1, PubMed

EGFR, Complex: A4:EGFR, PubMed

EPHA2, Complex: A4:EPHA2, PubMed

EPHB4, Complex: A4:EPHB4, PubMed

EVI2A, Complex: EVI2A:A4, PubMed

F151A, Complex: A4:F151A, PubMed

FAAH2, Complex: A4:FAAH2, PubMed

FCG3A, Complex: FCG3A:A4, PubMed

FGFR2, Complex: FGFR2:A4, PubMed

FND3A, Complex: FND3A:A4, PubMed

G3ST1, Complex: G3ST1:A4, PubMed

GIMA4, Complex: A4:GIMA4, PubMed

GIMA5, Complex: A4:GIMA5, PubMed

GLT12, Complex: A4:GLT12, PubMed

GNPTA, Complex: A4:GNPTA, PubMed

GOSR1, Complex: GOSR1:A4, PubMed

GOSR2, Complex: A4:GOSR2, PubMed

HAVR2, Complex: A4:HAVR2, PubMed

HG2A, Complex: HG2A:A4, PubMed

HRSL1, Complex: A4:HRSL1, PubMed

HTRA2, Complex: A4:HTRA2, PubMed

I18RA, Complex: I18RA:A4, PubMed

ICAM3, Complex: ICAM3:A4, PubMed

IEX1, Complex: A4:IEX1, PubMed

IGF1R, Complex: A4:IGF1R, PubMed

IGHM, Complex: A4:IGHM, PubMed

IGSF6, Complex: A4:IGSF6, PubMed

IKIP, Complex: IKIP:A4, PubMed

ILRL1, Complex: A4:ILRL1, PubMed

IOD3, Complex: IOD3:A4, PubMed

ITA6, Complex: A4:ITA6, PubMed

ITM2A, Complex: ITM2A:A4

ITM2B, Complex: ITM2B:A4, PubMed

JTB, Complex: A4:JTB, PubMed

KCE1L, Complex: KCE1L:A4, PubMed

KCT2, Complex: A4:KCT2, PubMed

KI2L3, Complex: KI2L3:A4, PubMed

LAIR1, Complex: LAIR1:A4, PubMed

LETM2, Complex: A4:LETM2, PubMed

LFA3, Complex: LFA3:A4, PubMed

LFNG, Complex: LFNG:A4, PubMed

LIGO2, Complex: A4:LIGO2, PubMed

LMAN1, Complex: A4:LMAN1, PubMed

LRC59, Complex: LRC59:A4, PubMed

LRP1B, Complex: A4:LRP1B, PubMed

LRP1, Complex: LRP1:A4, PubMed

LRP2, Complex: LRP2:A4, PubMed

LTMD1, Complex: A4:LTMD1, PubMed

MAG, Complex: A4:MAG, PubMed

MICU1, Complex: MICU1:A4, PubMed

MMGT1, Complex: A4:MMGT1, PubMed

MRAP2, Complex: MRAP2:A4

NADL2, Complex: A4:NADL2, PubMed

NDUB1, Complex: A4:NDUB1, PubMed

NDUB3, Complex: NDUB3:A4, PubMed

NDUB6, Complex: A4:NDUB6, PubMed

NICA, Complex: NICA:A4, PubMed

NOTC1, Complex: NOTC1:A4, PubMed

NTRK3, Complex: A4:NTRK3, PubMed

OSBL5, Complex: A4:OSBL5, PubMed

PCDA7, Complex: PCDA7:A4, PubMed

PCDGC, Complex: PCDGC:A4, PubMed

PCDGK, Complex: A4:PCDGK, PubMed

PCDGM, Complex: PCDGM:A4, PubMed

PLS1, Complex: PLS1:A4, PubMed

PMGT2, Complex: PMGT2:A4

PTGIS, Complex: A4:PTGIS, PubMed

PTPRO, Complex: A4:PTPRO, PubMed

QPCTL, Complex: QPCTL:A4, PubMed

RAGE, Complex: RAGE:A4, PubMed

RN183, Complex: RN183:A4, PubMed

ROR1, Complex: ROR1:A4, PubMed

SCO2, Complex: A4:SCO2

SDC1, Complex: A4:SDC1, PubMed

SEC20, Complex: SEC20:A4, PubMed

SERP1, Complex: A4:SERP1, PubMed

SGCG, Complex: A4:SGCG, PubMed

SIA10, Complex: A4:SIA10, PubMed

SIGIR, Complex: A4:SIGIR, PubMed

SIM11, Complex: A4:SIM11, PubMed

SPIT2, Complex: SPIT2:A4, PubMed

SRAC1, Complex: SRAC1:A4, PubMed

SRTM1, Complex: SRTM1:A4, PubMed

STML1, Complex: STML1:A4, PubMed

STML3, Complex: STML3:A4, PubMed

SUN5, Complex: SUN5:A4

SUSD3, Complex: SUSD3:A4, PubMed

SYJ2B, Complex: A4:SYJ2B, PubMed

SYT6, Complex: A4:SYT6, PubMed

T183A, Complex: A4:T183A, PubMed

TGFR2, Complex: TGFR2:A4, PubMed

TIE2, Complex: A4:TIE2, PubMed

TIM14, Complex: A4:TIM14, PubMed

TMM53, Complex: A4:TMM53, PubMed

TMX3, Complex: A4:TMX3, PubMed

TN13B, Complex: A4:TN13B, PubMed

TNF14, Complex: TNF14:A4, PubMed

TNR14, Complex: A4:TNR14, PubMed

TNR16, Complex: A4:TNR16, PubMed

TNR21, Complex: A4:TNR21, PubMed

TOM5, Complex: TOM5:A4, PubMed

UD110, Complex: UD110:A4, PubMed

USE1, Complex: USE1:A4, PubMed

VAMP3, Complex: A4:VAMP3, PubMed

VAPA, Complex: VAPA:A4, PubMed

VSIG4, Complex: VSIG4:A4, PubMed

YD002, Complex: A4:CD021.YD002, PubMed

Domains

AA: 31-131, PDBID: 1MWP, Subunit A, Seq Identity:100%, Amyloid A4 N-terminal heparin-binding

AA: 132-188, PDBID: 1OWT, Subunit A, Seq Identity:100%, Copper-binding of amyloid precursor, CuBD

AA: 290-342, PDBID: 1AAP, Subunit A, Seq Identity:100%, Kunitz/Bovine pancreatic trypsin inhibitor domain

AA: 366-548, PDBID: 1TKN, Subunit A, Seq Identity:100%, E2 domain of amyloid precursor protein

AA: 675-713, PDBID: 1AMB, Subunit A, Seq Identity:100%, Beta-amyloid peptide (beta-APP)

AA: 716-766, PDBID: 1M7E, Subunit F, Seq Identity:100%, beta-amyloid precursor protein C-terminus

UniProt annotation for A4_HUMAN » Amyloid beta A4 protein
FUNCTION: 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.

FUNCTION: 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. Also bind GPC1 in lipid rafts.

FUNCTION: Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain.

FUNCTION: The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.

FUNCTION: N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).

SUBUNIT: Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and, NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, FPRL1, APPBP1, IB1, KNS2 (via its TPR domains) (By similarity), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Amyloid beta-42 binds CHRNA7 in hippocampal neurons. Beta-amyloid associates with HADH2. Soluble APP binds, via its N-terminal head, to FBLN1. Interacts with CPEB1 and AGER (By similarity). Interacts with ANKS1B and TNFRSF21. Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; this is promoted by heparin binding. Beta-amyloid protein 40 interacts with S100A9. CTF-alpha product of APP interacts with GSAP. Interacts with SORL1. Interacts with PLD3.

TISSUE SPECIFICITY: Expressed in all fetal tissues examined with highest levels in brain, kidney, heart and spleen. Weak expression in liver. In adult brain, highest expression found in the frontal lobe of the cortex and in the anterior perisylvian cortex- opercular gyri. Moderate expression in the cerebellar cortex, the posterior perisylvian cortex-opercular gyri and the temporal associated cortex. Weak expression found in the striate, extra- striate and motor cortices. Expressed in cerebrospinal fluid, and plasma. Isoform APP695 is the predominant form in neuronal tissue, isoform APP751 and isoform APP770 are widely expressed in non- neuronal cells. Isoform APP751 is the most abundant form in T- lymphocytes. Appican is expressed in astrocytes.

INDUCTION: Increased levels during neuronal differentiation.

DOMAIN: The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells.

DOMAIN: The NPXY sequence motif found in many tyrosine- phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C- terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The NPXY site is also involved in clathrin-mediated endocytosis.

DISEASE: Alzheimer disease 1 (AD1) OMIM: 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.

DISEASE: Cerebral amyloid angiopathy, APP-related (CAA-APP) OMIM: 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. Note=The disease is caused by mutations affecting the gene represented in this entry.

MISCELLANEOUS: Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between beta-amyloid molecules resulting in beta-amyloid-metal aggregates. The affinity for copper is much higher than for other transient metals and is increased under acidic conditions. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding.

UniProt features for A4_HUMAN » Amyloid beta A4 protein
SIGNAL 1 17
CHAIN 18 770 Amyloid beta A4 protein.
CHAIN 18 687 Soluble APP-alpha.
CHAIN 18 671 Soluble APP-beta.
CHAIN 18 286 N-APP.
CHAIN 672 770 C99.
CHAIN 672 713 Beta-amyloid protein 42.
CHAIN 672 711 Beta-amyloid protein 40.
CHAIN 688 770 C83.
PEPTIDE 688 713 P3(42).
PEPTIDE 688 711 P3(40).
CHAIN 691 770 C80.
CHAIN 712 770 Gamma-secretase C-terminal fragment 59.
CHAIN 714 770 Gamma-secretase C-terminal fragment 57.
CHAIN 721 770 Gamma-secretase C-terminal fragment 50 (By similarity).
CHAIN 740 770 C31.
DOMAIN 291 341 BPTI/Kunitz inhibitor.
REGION 96 110 Heparin-binding.
REGION 181 188 Zinc-binding.
REGION 391 423 Heparin-binding.
REGION 491 522 Heparin-binding.
REGION 523 540 Collagen-binding.
REGION 732 751 Interaction with G(o)-alpha.
MOTIF 724 734 Basolateral sorting signal.
MOTIF 759 762 NPXY motif; contains endocytosis signal.
SITE 144 144 Required for Cu(2+) reduction.
SITE 301 302 Reactive bond.
SITE 671 672 Cleavage; by beta-secretase.
SITE 672 673 Cleavage; by caspase-6; when associated with variant 670-N-L-671.
SITE 687 688 Cleavage; by alpha-secretase.
SITE 690 691 Cleavage; by theta-secretase.
SITE 704 704 Implicated in free radical propagation (By similarity).
SITE 706 706 Susceptible to oxidation.
SITE 711 712 Cleavage; by gamma-secretase; site 1.
SITE 713 714 Cleavage; by gamma-secretase; site 2.
SITE 720 721 Cleavage; by gamma-secretase; site 3.
SITE 739 740 Cleavage; by caspase-6, caspase-8 or caspase-9.
DISULFID 38 62
DISULFID 73 117
DISULFID 98 105
DISULFID 133 187
DISULFID 144 174
DISULFID 158 186
DISULFID 291 341
DISULFID 300 324
DISULFID 316 337
Amino Acid Sequence for A4_HUMAN » Amyloid beta A4 protein
MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSAMSQSLL KTTQEPLARD PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA KHRERMSQVM REWEEAERQA KNLPKADKKA VIQHFQEKVE SLEQEAANER QQLVETHMAR VEAMLNDRRR LALENYITAL QAVPPRPRHV FNMLKKYVRA EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER MNQSLSLLYN VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEVEPV DARPAADRGL TTRPGSGLTN IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAEDVGSNKG AIIGLMVGGV VIATVIVITL VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYENP TYKFFEQMQN