Taxonomic distribution of proteins containing A4_EXTRA domains

The tree below includes only several representative species and genera. The complete taxonomic breakdown of all proteins containing A4_EXTRA domains can be accessed here. Click the counts or percentage values to display the corresponding proteins.

Role of the beta-amyloid precursor protein in Alzheimer's disease.

Ashall F, Goate AM
Trends Biochem Sci. 1994; 19: 42-6

Deposition of beta-amyloid peptide in the brain is an early event in Alzheimer's disease, the most common cause of dementia. Studies of the beta-amyloid precursor protein (APP), which gives rise to beta-amyloid, are rapidly leading to a better understanding of the biochemical basis of the disease--a prerequisite for rational drug development.

Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer's disease.

Dyrks T, Weidemann A, Multhaup G, Salbaum JM, Lemaire HG, Kang J, Muller-Hill B, Masters CL, Beyreuther K
EMBO J. 1988; 7: 949-57

The precursor of the Alzheimer's disease-specific amyloid A4 protein is an integral, glycosylated membrane protein which spans the bilayer once. The carboxy-terminal domain of 47 residues was located at the cytoplasmic site of the membrane. The three domains following the transient signal sequence of 17 residues face the opposite side of the membrane. The C-terminal 100 residues of the precursor comprising the amyloid A4 part and the cytoplasmic domain have a high tendency to aggregate, and proteinase K treatment results in peptides of the size of amyloid A4. This finding suggests that there is a precursor-product relationship between precursor and amyloid A4 and we conclude that besides proteolytic cleavage other events such as post-translational modification and membrane injury are primary events that precede the release of the small aggregating amyloid A4 subunit.

A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors.

Ponte P, Gonzalez-DeWhitt P, Schilling J, Miller J, Hsu D, Greenberg B, Davis K, Wallace W, Lieberburg I, Fuller F
Nature. 1988; 331: 525-7

The amyloid proteins isolated from neuritic plaques and the cerebrovasculature of Alzheimer's disease are self-aggregating moieties termed A4 protein and beta-protein, respectively. A putative A4 amyloid precursor (herein termed A4(695] has been characterized by analysis of a human brain complementary DNA. We report here the sequence of a closely related amyloid cDNA, A4(751), distinguished from A4(695) by the presence of a 168 base-pair (bp) sequence which adds 57 amino acids to, and removes one residue from, the predicted A4(695) protein. The peptide predicted from this insert is very similar to the Kunitz family of serine proteinase inhibitors. The two A4-specific messenger RNAs are differentially expressed: in a limited survey, A4(751) mRNA appears to be ubiquitous, whereas A4(695) mRNA has a restricted pattern of expression which includes cells from neuronal tissue. These data may have significant implications for understanding amyloid deposition in Alzheimer's disease.

Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease.

Tanzi RE, McClatchey AI, Lamperti ED, Villa-Komaroff L, Gusella JF, Neve RL
Nature. 1988; 331: 528-30

Amyloid B-protein/amyloid A4 is a peptide present in the neuritic plaques, neurofibrillary tangles and cerebrovascular deposits in patients with Alzheimer's disease and Down's syndrome (trisomy 21) and may be involved in the pathogenesis of Alzheimer's disease. Recent molecular genetic studies have indicated that amyloid protein is encoded as part of a larger protein by a gene on human chromosome 21 (refs 6-9). The amyloid protein precursor (APP) gene is expressed in brain and in several peripheral tissues, but the specific biochemical events leading to deposition of amyloid are not known. We have now screened complementary DNA libraries constructed from peripheral tissues to determine whether the messenger RNA encoding APP in these tissues is identical to that expressed in brain, and we identify a second APP mRNA that encodes an additional internal domain with a sequence characteristic of a Kunitz-type serine protease inhibitor. The alternative APP mRNA is present in both brain and peripheral tissues of normal individuals and those with Alzheimer's disease, but its pattern of expression differs from that of the previously reported APP mRNA.