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amyloid precursor protein [APP]-751

Terminology of peptide cleavage fragments: - A4/beta amyloid: peptide between beta & gamma secretase sites - P3: peptide between alpha & gamma secretase sites - AICD: peptide C terminal to gamma secretase site - C31: C terminal caspase cleavage peptide [14] - C83: peptide C terminal to alpha secretase site, substrate for gamma secretase - C99: peptide C terminal to beta secretase site, substrate for gamma secretase Function: 1) may function as a kinesin-1 membrane receptor [10] a) mediated by binding of APP to the kinesin light chain subunit of kinesin-1 b) facilitates fast anterograde axonal transport of a compartment containing several proteins c) see 'role of APP in axonal transport' 2) may function as a cell surface receptor which couples to signaling pathways through GTP-binding protein G(O) 3) apoptosis [9,16] a) APP is cleaved by caspase 3 at DNVD197/S, DYAD219/G & VEVD720/A (predominant site) b) caspase mediated proteolysis of APP increases A4/beta amyloid formation c) superphysiologic levels of TGF-beta2 bind to APP & activate apoptosis via heterotrimeric G protein Go, c-Jun N-terminal kinase, NADPH oxidase & caspase 3 [16] 4) KPI containing forms can inhibit serine proteases - trypsin, chymotrypsin, factor XIa 5) soluble alpha-APPs may act as autocrine factor, neuroprotective or neuritotrophic factor [11] 6) degradation: a) protease cleavage: 1] APP-secretases 2] caspases (3, 6, 8, 9) [14] 3] kallikrein-6 4] THOP1 b) increased sumoylation of APP with poly(SUMO3)chains may inhibit APP proteolysis [13] c) ANKS1B may modulate APP processing 7) interacts with COL25A1 8) several APP binding proteins have been described (see amyloid beta A4 precursor protein binding family) Structure: - APP-751 & APP-770 contain a Kunitz protease inhibitor domain Compartment: 1) in polarized epithelial cells, APP is targeted largely to the basolateral membrane; less is targeted to the apical membrane 2) in neurons, APP is present in vesicles in axon terminals a) fast anterograde axonal transport b) retrograde axonal transport 3) somatodendritic plasma membranes a) lipid rafts (most NOT in lipid rafts) b) cleavage (via BACE) may occur in lipid rafts Alternative splicing: - at least 10 alternately spliced forms including: a) APP-695 (neuronal) b) APP-751 (predominant form in other tissues) c) APP-770 Expression: 1) virtually all peripheral cells express APP & generate A4/beta 2) APP-695 is expressed preferentially in neuronal tissue 3) APP-751 is the predominant form in other tissues 4) in the brain: neurons, astrocytes, microglia, endothelial cells & smooth muscle cells Pathology: - precursor protein for A4/beta amyloid deposited in senile plaques of Alzheimer's disease Laboratory: - amyloid precursor protein Ag in tissue Comparative biology: - highly conserved in evolution - expressed in all mammals - an APP homolog is found in Drosophila

Interactions

molecular events

Related

APP gene

General

amyloid precursor like protein (APLP) family protein precursor serine protease inhibitor; serpin

Properties

SIZE: MW = 110-140 COMPARTMENT: plasma membrane FORM: APP-751 MOTIF: cysteine-rich region sulfotyrosine site MODIFICATION: sulfate Zn+2-binding site acidic region MOTIF: acidic residue (SEVERAL) Kunitz-type serine protease inhibitor [KPI] domain {289-345} MOTIF: cysteine residue {X+0} MODIFICATION: cysteine residue {X+X5} cysteine residue {X+X1} MODIFICATION: cysteine residue {X+X3} cysteine residue {X+X2} MODIFICATION: cysteine residue {X+X4} cysteine residue {X+X3} MODIFICATION: cysteine residue {X+X1} cysteine residue {X+X4} MODIFICATION: cysteine residue {X+X2} cysteine residue {X+X5} MODIFICATION: cysteine residue {X+0} FOR-BINDING-OF: serine protease binding site FOR-BINDING-OF: heparan sulfate binding site FOR-BINDING-OF: collagenase-4 MOTIF: O-glycosylation site N-glycosylation site (2) domain MOTIF: proteolytic site transmembrane domain {683-704} Thr phosphorylation site {T710} Ser phosphorylation site {S711} binding site FOR-BINDING-OF: Go protein NPXY motif NAME: NPXY motif FOR-BINDING-OF: amyloid beta A4 protein-binding family B member 1 MOTIF-SEQUENCE: Asn-Pro-Thr-Tyr PRECURSOR-FOR: protease nexin-2 COMPARTMENT: extracellular compartment MOTIF: cysteine-rich region sulfotyrosine site MODIFICATION: sulfate Zn+2-binding site acidic region MOTIF: acidic residue (SEVERAL) Kunitz-type serine protease inhibitor [KPI] domain MOTIF: cysteine residue {X+0} MODIFICATION: cysteine residue {X+X5} cysteine residue {X+X1} MODIFICATION: cysteine residue {X+X3} cysteine residue {X+X2} MODIFICATION: cysteine residue {X+X4} cysteine residue {X+X3} MODIFICATION: cysteine residue {X+X1} cysteine residue {X+X4} MODIFICATION: cysteine residue {X+X2} cysteine residue {X+X5} MODIFICATION: cysteine residue {X+0} FOR-BINDING-OF: serine protease binding site FOR-BINDING-OF: heparan sulfate binding site FOR-BINDING-OF: collagenase-4 MOTIF: O-glycosylation site N-glycosylation site (2) SECRETED-BY: neuron platelet INHIBITS: coagulation factor XIa INHIBITS: collagenase-4 serine protease MISC-INFO: 1/2life 20-60 MINUTES

Database Correlations

OMIM 104760 MORBIDMAP 104760 UniProt P05067 Entrez Gene 351

References

  1. Katzman R, Saitoh T. Advances in Alzheimer's disease. FASEB J. 1991 Mar 1;5(3):278-86. Review. PMID: 2001787
  2. Kang J et al The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733 1987 PMID: 2881207
  3. Ponte P et al A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature 331:525 1988 PMID: 2893289
  4. Tanzi RE et al Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease. Nature 331:528 1988 PMID: 2893290
  5. Kitaguchi N et al Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity. Nature 331:530 1988 PMID: 2893291
  6. Haass C, Koo EH, Mellon A, Hung AY, Selkoe DJ. Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature. 1992 Jun 11;357(6378):500-3. PMID: 1608449
  7. Nishimoto I, Okamoto T, Matsuura Y, Takahashi S, Okamoto T, Murayama Y, Ogata E. Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o) Nature. 1993 Mar 4;362(6415):75-9. PMID: 8446172
  8. Miyazaki K, Hasegawa M, Funahashi K, Umeda M. A metalloproteinase inhibitor domain in Alzheimer amyloid protein precursor. Nature. 1993 Apr 29;362(6423):839-41. PMID: 8479521
  9. Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, LeBlanc A, Smith D, Rigby M, Shearman MS, Clarke EE, Zheng H, Van Der Ploeg LH, Ruffolo SC, Thornberry NA, Xanthoudakis S, Zamboni RJ, Roy S, Nicholson DW. Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell. 1999 Apr 30;97(3):395-406. PMID: 10319819
  10. Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature. 2001 Dec 6;414(6864):643-8. PMID: 11740561
  11. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PMID: 11274343
  12. Entrez Gene :accession 351
  13. Li Y, Wang H, Wang S, Quon D, Liu YW, Cordell B. Positive and negative regulation of APP amyloidogenesis by sumoylation. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):259-64. Epub 2002 Dec 27. Erratum in: Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):9102. PMID: 12506199
  14. Lu DC, Rabizadeh S, Chandra S, Shayya RF, Ellerby LM, Ye X, Salvesen GS, Koo EH, Bredesen DE. A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor. Nat Med. 2000 Apr;6(4):397-404. PMID: 10742146
  15. Pietrzik CU et al, FE65 constitutes the functional link between the low-density lipoprotein receptor-related protein and the amyloid precursor protein. J Neurosci. 2004 Apr 28;24(17):4259-65. PMID: 15115822
  16. Hashimoto Y, Chiba T, Yamada M, Nawa M, Kanekura K, Suzuki H, Terashita K, Aiso S, Nishimoto I, Matsuoka M. Transforming growth factor beta2 is a neuronal death-inducing ligand for amyloid-beta precursor protein. Mol Cell Biol. 2005 Nov;25(21):9304-17. PMID: 16227582
  17. Shubert D, Schroeder R, LaCorbiere M, Saitoh T, Cole G. Amyloid beta protein precursor is possibly a heparan sulfate proteoglycan core protein. Science 241:223 PMID: 2968652

Component-of

molecular complex