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12  structures 88  species 0  interactions 356  sequences 16  architectures

Family: APP_N (PF02177)

Summary: Amyloid A4 N-terminal heparin-binding

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This is the Wikipedia entry entitled "Growth factor-like domain". More...

Growth factor-like domain Edit Wikipedia article

Amyloid precursor N-terminal
1mwp gfld.png
The GFLD region of amyloid precursor protein
Identifiers
Symbol APP_CU_bd
Pfam PF02177
InterPro IPR008154
SMART SM00006
SCOP 1mwp
SUPERFAMILY 1mwp

A growth factor-like domain (GFLD) is a protein domain structurally related to epidermal growth factor, which has a high binding affinity for the epidermal growth factor receptor. As structural domains within larger proteins, GFLD regions commonly bind calcium ions. A subtype present in the N-terminal region of the amyloid precursor protein is a member of the heparin-binding class of GFLDs and may itself have growth factor function, particularly in promoting neuronal development.

[edit] References

  • Rossjohn J, Cappai R, Feil SC, Henry A, McKinstry WJ, Galatis D, Hesse L, Multhaup G, Beyreuther K, Masters CL, Parker MW. (1999). Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein. Nat Struct Biol 6(4):327-31.

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Amyloid A4 N-terminal heparin-binding Provide feedback

This N-terminal domain of APP, amyloid precursor protein, is the heparin-binding domain of the protein. this region is also responsible for stimulation of neurite outgrowth. The structure reveals both a highly charged basic surface that may interact with glycosaminoglycans in the brain and an abutting hydrophobic surface that is proposed to play an important functional role such as in dimerisation or ligand-binding. Structural similarities with cysteine-rich growth factors, taken together with its known growth-promoting properties, suggest the APP N-terminal domain could function as a growth factor in vivo [1].

Literature references

  1. 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. 1999;6:327-331.: Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein. PUBMED:10201399 EPMC:10201399


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR015849

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 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 beta-x-alpha-beta-loop-beta topology [PUBMED:10201399].

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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Full
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Representative proteomes NCBI
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  Seed
(15)
Full
(356)
Representative proteomes NCBI
(317)
Meta
(3)
RP15
(20)
RP35
(28)
RP55
(61)
RP75
(114)
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  Seed
(15)
Full
(356)
Representative proteomes NCBI
(317)
Meta
(3)
RP15
(20)
RP35
(28)
RP55
(61)
RP75
(114)
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

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Pfam alignments:

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Curation and family details

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Curation View help on the curation process

Seed source: Alignment kindly provided by SMART
Previous IDs: A4_EXTRA;
Type: Domain
Author: SMART
Number in seed: 15
Number in full: 356
Average length of the domain: 98.20 aa
Average identity of full alignment: 60 %
Average coverage of the sequence by the domain: 14.97 %

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 22.1 21.6
Trusted cut-off 22.1 31.9
Noise cut-off 19.7 21.5
Model length: 102
Family (HMM) version: 11
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_N domain has been found. There are 12 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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