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23  structures 84  species 0  interactions 340  sequences 18  architectures

Family: APP_Cu_bd (PF12924)

Summary: Copper-binding of amyloid precursor, CuBD

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Copper-binding of amyloid precursor, CuBD Provide feedback

This short domain, part of the extra-cellular N-terminus of the amyloid precursor protein, APP, can bind both copper and zinc, CuBD. The structure of Cu2+-bound CuBD reveals that the metal ligands are His147, His151, Tyr168 and two water molecules, which are arranged in a square pyramidal geometry. The structure of Cu+-bound CuBD is almost identical to the Cu2+-bound structure except for the loss of one of the water ligands. The geometry of the site is unfavourable for Cu+, thus providing a mechanism by which CuBD could readily transfer Cu ions to other proteins.

Literature references

  1. Kong GK, Adams JJ, Harris HH, Boas JF, Curtain CC, Galatis D, Masters CL, Barnham KJ, McKinstry WJ, Cappai R, Parker MW;, J Mol Biol. 2007;367:148-161.: Structural studies of the Alzheimer's amyloid precursor protein copper-binding domain reveal how it binds copper ions. PUBMED:17239395 EPMC:17239395


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR011178

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 [PUBMED:16301322, PUBMED:16364896]. 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 [PUBMED:16406235]. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, 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 [PUBMED:16406235]. 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 [PUBMED:12611883]. 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 entry represents a copper-binding domain found within the extracellular domain, which is at the N-terminal of amyloidogenic glycoproteins such as amyloid-beta precursor protein (APP, or A4). The copper-binding domain has a dodecin-like fold consisting of a 2-layer alpha/beta topology [PUBMED:12611883].

More information about these protein can be found at Protein of the Month: Amyloid-beta Precursor Protein [PUBMED:].

Gene Ontology

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Domain organisation

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Alignments

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(17)
Full
(340)
Representative proteomes NCBI
(306)
Meta
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RP35
(27)
RP55
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RP75
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

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  Seed
(17)
Full
(340)
Representative proteomes NCBI
(306)
Meta
(0)
RP15
(20)
RP35
(27)
RP55
(61)
RP75
(111)
Alignment:
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  Seed
(17)
Full
(340)
Representative proteomes NCBI
(306)
Meta
(0)
RP15
(20)
RP35
(27)
RP55
(61)
RP75
(111)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download    
Gzipped Download   Download   Download   Download   Download   Download   Download    

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

Pfam alignments:

HMM logo

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Trees

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: manual
Previous IDs: none
Type: Domain
Author: Coggill P
Number in seed: 17
Number in full: 340
Average length of the domain: 57.50 aa
Average identity of full alignment: 64 %
Average coverage of the sequence by the domain: 8.54 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 26.4 26.4
Trusted cut-off 28.1 28.1
Noise cut-off 24.8 26.3
Model length: 58
Family (HMM) version: 2
Download: download the raw HMM for this family

Species distribution

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the APP_Cu_bd domain has been found. There are 23 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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