SSF56491

A heparin-binding domain

SUPERFAMILY entry
Member databaseSUPERFAMILY
SUPERFAMILY typehomologous superfamily

Description
Imported from IPR036454

Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques
[2, 3, 7]
. Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.

APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products
[4, 6]
. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility
[4]
. APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death
[1, 6]
. The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.

APP can be processed by different sets of enzymes:


 * In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling).
 * In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.


This superfamily represents a heparin-binding domain found at the N-terminal of the extracellular domain, which is itself found at the N-terminal of amyloidogenic glycoproteins such as amyloid-beta precursor protein (APP, or A4). The core of the heparin-binding domain has an unusual disulphide-rich fold, consisting of a β-x-α-β-loop-β topology
[5]
.

References
Imported from IPR036454

1.Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis. Barnham KJ, McKinstry WJ, Multhaup G, Galatis D, Morton CJ, Curtain CC, Williamson NA, White AR, Hinds MG, Norton RS, Beyreuther K, Masters CL, Parker MW, Cappai R. J. Biol. Chem. 278, 17401-7, (2003). View articlePMID: 12611883

2.Structural changes of region 1-16 of the Alzheimer disease amyloid beta-peptide upon zinc binding and in vitro aging. Zirah S, Kozin SA, Mazur AK, Blond A, Cheminant M, Segalas-Milazzo I, Debey P, Rebuffat S. J. Biol. Chem. 281, 2151-61, (2006). View articlePMID: 16301322

3.Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Neuron 48, 913-22, (2005). View articlePMID: 16364896

4.The amyloid precursor protein and postnatal neurogenesis/neuroregeneration. Chen Y, Tang BL. Biochem. Biophys. Res. Commun. 341, 1-5, (2006). View articlePMID: 16406235

5.Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein. Rossjohn J, Cappai R, Feil SC, Henry A, McKinstry WJ, Galatis D, Hesse L, Multhaup G, Beyreuther K, Masters CL, Parker MW. Nat. Struct. Biol. 6, 327-31, (1999). View articlePMID: 10201399

6.Amyloid beta: structure, biology and structure-based therapeutic development. Chen GF, Xu TH, Yan Y, Zhou YR, Jiang Y, Melcher K, Xu HE. Acta Pharmacol Sin 38, 1205-1235, (2017). PMID: 28713158

7.Comprehensive Review on Alzheimer's Disease: Causes and Treatment. Breijyeh Z, Karaman R. Molecules 25, (2020). PMID: 33302541

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our Privacy Notice and Terms of Use.