Amyloid-b Precursor Protein

 

Family Ties

APP belongs to a protein family that includes APP-like isoforms (APLP-1 and APLP-2 in mammals), which lack the Ab sequence.  There appears to be some functional redundancy between APP and its isoforms in mammals, as APLP-1 or APLP-2 can partially compensate for the loss of the APP gene in mouse models.  Triple mutants involving APP, APLP-1 and APLP-2 are lethal. 

 

What InterPro Tells Us

P05067 Human Amyloid-b Precursor Protein

 

InterPro Domain Architecture

 

InterPro Entry

Signatures

Graphical Match

Method Name

IPR002223

G3DSA:4.10.410.10

Prot_inh_Kunz-m

IPR002223

PD000222

Prot_inh_Kunz-m

IPR002223

PF00014

Kunitz_BPTI

IPR002223

PR00759

BASICPTASE

IPR002223

PS00280

BPTI_KUNITZ_1

IPR002223

PS50279

BPTI_KUNITZ_2

IPR002223

SM00131

KU

IPR002223

SSF57362

Prot_inh_Kunz-m

IPR008154

PF02177

A4_EXTRA

IPR008154

SM00006

A4_EXTRA

IPR008154

SSF56491

A4_extra

IPR008155

PR00203

AMYLOIDA4

IPR008155

PS00319

A4_EXTRA

IPR008155

PS00320

A4_INTRA

IPR013803

G3DSA:4.10.230.10

Beta‑amyloid peptide

IPR013803

PF03494

Beta-APP

IPR013803

PR00204

BETAAMYLOID

Structural Features

 

 

 

1aap

1aap A,B

 

1mwp

1mwpA   

 

1owt

1owtA   

 

1tkn

1tknA  

 

2beq

2beq A-E  

 

3.90.570.10.1

1mwpA0   

 

4.10.230.10.1

1aml00  

 

4.10.410.10.3

1aapA0 

 

a.47.4.1

d1tkna_  

 

d.170.2.1

d1mwpa_ 

 

d.230.3.1

d1owta_  

 

g.8.1.1

d1aapa_ 

 

j.42.1.1

d1amb__ 

 

Structural Predictions

 

 

 

MB_P05067

 

 

 

From the graphical match above, you can see that the signatures are all grouped into four InterPro entries for human amyloid-b precursor protein, APP.  InterPro entries group together all the signatures that represent the same sequence found in the same set of proteins.  These entries provide a family grouping of APP proteins, as well as subdividing APP into three constituent domains (the remaining domains are not currently represented by any signatures). 

FAMILY Entries

Ø      IPR008155: Amyloidogenic glycoprotein family, represented by three signatures: PR00203 (PRINTS), PS00319 (PROSITE), and PS00320 (PROSITE).

DOMAIN Entries

Ø      IPR008154: N-terminal extracellular domain.  Represented by three signatures: PF02177 (PFAM), SM00006 (SMART), and SSF56491 (SUPERFAMILY). 

Ø      IPR002223: Kunitz proteinases inhibitor I2 domain (which is found in several other protein families as well).  Represented by eight signatures: G3DSA:4.10.410.10 (GENE3D), PD000222 (PRODOM), PF00014 (PFAM), PR00759 (PRINTS), PS00280 (PROSITE), PS50279 (PROSITE), SM00131 (SMART), and SSF57362 (SUPERFAMILY).

Ø      IPR013803: b-amyloid peptide that is cleaved from the APP protein (prior to the C-terminal cytoplasmic domain).  Represented by three signatures: G3DSA:4.10.230.10 (GENE3D), PF03494 (PFAM), and PR00204 (PRINTS).

 

The remaining fourteen entries in the table above give information on the known and predicted structure of this protein.  The first thirteen entries present known structural data from the structural database PDB (green stripe) and the structural classification databases CATH (pink stripe) and SCOP (black stripe) (the names such as 1aapA0 are derived from the PDB entry upon which they are based, here PDB entry 1aap, chain A).  There are five PDB entries that represent this protein: 1aap (chain A and B), 1mwp (chain A), 1owt (chain A), 1tkn (chain A), and 2beg (chains A to E).  The CATH and SCOP entries provide a structural classification for each domain represented in the PDB data, and relate it to other structures in the PDB database.  CATH has classified three of the PDB structures, while SCOP classifies all five:

Ø      N-terminal extracellular heparin-binding domain is represented by 3.90.570.10.1 (CATH) and d.170.2.1 (SCOP), and has a disulphide-rich alpha+beta fold

Ø      Extracellular copper-binding domain is represented by d.230.3.1 (SCOP), and has a 2-layer beta/alpha/beta fold

Ø      Kunitz-type inhibitor domain is represented by 4.10.410.10.3 (CATH) and g.8.1.1 (SCOP), and has a disulphide-rich alpha+beta fold

Ø      CAPPD extracellular domain is represented by a.47.4.1 (SCOP), and has an alpha-helical bundle fold

Ø      Amyloid-b peptide is represented by 4.10.230.10.1 (CATH) and j.42.1.1 (SCOP), and has an irregular fold

It is interesting to note that two SCOP classifications subdivide the InterPro entry IPR008154 (N-terminal extracellular domain) into two structural subdomains: the heparin-binding subdomain and the copper-binding subdomain.

            The remaining entry is for the structural prediction, MB_P05067, from the homology model database ModBase (yellow stripe).  The homology model provides information on the predicted structure for regions of the proteins that have no known structure, here the region between the Kunitz-type inhibitor domain and the CAPPD extracellular domain.

 

What the Structure Tells Us

 

            Structures associated with APP can be viewed using AstexViewer®, which is linked from the Match Table via the logo  on the InterPro page (please note, there is no link directly from this page to the AstexViewer®, therefore you need to go to the  link on the InterPro page for P05067).  The AstexViewer® displays the PDB structure with the specific CATH or SCOP domain highlighted.

            There are structures available for various APP proteins in the Protein Data Bank (PDB).  A detailed description and visualisation of the structural features of this protein can be found at the PDB ‘Molecule of the Month’.  The crystallographic structures of APP have provided insight into several aspects of Alzheimer’s disease.

 

Next:   Table of APP Proteins

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