cDNA sequence analysis, chromosomal assignment and expression pattern of the gene coding for integral membrane protein 2B

Giliberto

Journal of Biological Chemistry

et al. 2005

134

160

Alzheimer disease (AD), the most common senile dementia, is characterized by amyloid plaques, vascular amyloid, neurofibrillary tangles, and progressive neurodegeneration. Amyloid is mainly composed by amyloid-␤ (A␤) peptides, which are derive from processing of the ␤-amyloid precursor protein (APP), better named amyloid-␤ precursor protein (A␤PP), by secretases. The A␤PP intracellular domain (AID), which is released together with A␤, has signaling function, since it modulates apoptosis and transcription. Despite its biological and pathological importance, the mechanisms regulating A␤PP processing are poorly understood. As cleavage of other ␥-secretase substrates is regulated by membrane bound proteins, we have postulated the existence of integral membrane proteins that bind A␤PP and regulate its processing. Here, we show that BRI2, a type II membrane protein, interacts with A␤PP. Interestingly, 17 amino acids corresponding to the NH 2 -terminal portion of A␤ are necessary for this interaction. Moreover, BRI2 expression regulates A␤PP processing resulting in reduced A␤ and AID levels. Altogether, these findings characterize the BRI2-A␤PP interaction as a regulatory mechanism of A␤PP processing that inhibits A␤ production. Notably, BRI2 mutations cause familial British (FBD) and Danish dementias (FDD) that are clinically and pathologically similar to AD. Finding that BRI2 pathogenic mutations alter the regulatory function of BRI2 on A␤PP processing would define dysregulation of A␤PP cleavage as a pathogenic mechanism common to AD, FDD, and FBD. A␤PP1 is an ubiquitous type I transmembrane protein (1, 2) that undergoes a series of endoproteolytic events (3-5). A␤PP is first cleaved at the plasma membrane or in intracellular organelles by ␤-secretase (6). While the ectodomain is released extracellularly (sAPP␤) or into the lumen of intracellular compartments, the COOH-terminal fragment of 99 amino acids (C99) remains membrane bound. In a second, intramembranous proteolytic event, C99 is cleaved, with somewhat lax site specificity, by the ␥-secretase. Two peptides are released in a 1:1 stoichiometric ratio: the amyloidogenic A␤ peptide, consisting of 2 major species of 40 and 42 amino acids (A␤40 and A␤42, respectively), and an intracellular product named AID or AICD, which is very short-lived and has been identified only recently (7-9). In an alternative, nonamyloidogenic proteolytic pathway, A␤PP is first processed by ␣-secretase in the A␤ sequence leading to the production of the sAPP␣ ectodomain and the membrane-bound COOH-terminal fragment of 83 amino acids (C83). C83 is also cleaved by the ␥-secretase into the P3 and AID peptides. While A␤ is implicated in the pathogenesis of Alzheimer disease, AID mediates most of the A␤PP signaling functions. A pathogenic role for A␤PP processing in AD has been ascertained by the finding that mutations in presenilins (10 -13), key components of the ␥-secretase, and A␤PP (14) cause autosomal dominant familial forms of AD. Thus, because of its biological and pathological import...

mentioning

confidence: 55%

The Familial Dementia BRI2 Gene Binds the Alzheimer Gene Amyloid-β Precursor Protein and Inhibits Amyloid-β Production

Giliberto

Journal of Biological Chemistry

et al. 2005

134

160

Proc. Natl. Acad. Sci. U.S.A.

“…1), purified from leptomeningeal vessels of an affected Danish patient, yielded the sequence SNXFAIRHFENKFAVE that represented Ϸ5% of the expected protein yield. BLASTP homology search (http:͞͞www.ncbi.nlm.nih.gov͞blast) of this sequence indicated homology with two putative integral transmembrane proteins named E3-16 (AF092128) and E25B (or ITM2B protein) (5,6). The amino acid sequence also had homology to the recently described ABri peptide starting at position three (4).…”

Section: Resultsmentioning

confidence: 80%

A decamer duplication in the 3′ region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred

Vidal

Révész

Rostagno

et al. 2000

284

330

Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica, is an autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia, and dementia. Neuropathological findings include severe widespread cerebral amyloid angiopathy, hippocampal plaques, and neurofibrillary tangles, similar to Alzheimer's disease. N-terminal sequence analysis of isolated leptomeningeal amyloid fibrils revealed homology to ABri, the peptide originated by a point mutation at the stop codon of gene BRI in familial British dementia. Molecular genetic analysis of the BRI gene in the Danish kindred showed a different defect, namely the presence of a 10-nt duplication (795-796insTTTAATTTGT) between codons 265 and 266, one codon before the normal stop codon 267. The decamer duplication mutation produces a frame-shift in the BRI sequence generating a larger-than-normal precursor protein, of which the amyloid subunit (designated ADan) comprises the last 34 C-terminal amino acids. This de novo-created amyloidogenic peptide, associated with a genetic defect in the Danish kindred, stresses the importance of amyloid formation as a causative factor in neurodegeneration and dementia.

Journal of Biological Chemistry

“…Recently we and others have identified three substrates, tumor necrosis factor ␣ (14, 22), Bri2 (24), and the FasL (23), for intramembrane proteolysis by SPPL2a/b. We now compared the processing of two homologous Bri proteins, Bri2 and Bri3 (30,34) (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Substrate Requirements for SPPL2b-dependent Regulated Intramembrane Proteolysis

Martin¹,

Fluhrer

Haass

2009

Intramembrane proteolysis is now widely recognized as an important physiological pathway required for reverse signaling and membrane protein degradation. Aspartyl intramembrane cleaving proteases of the GXGD-type play an important regulatory role in health and disease. Besides ␥-secretase/presenilin, signal peptide peptidase (SPP) and SPP-like (SPPL) peptidases also belong to the family of GXGD-type aspartyl proteases. Although recently the first SPPL2a/b substrates have been identified, very little is known about substrate requirements, which allow them to be efficiently processed within the membrane. We demonstrate that similar to ␥-secretase substrates, intramembrane proteolysis of Bri2 (Itm2b) is greatly facilitated by an initial shedding event mediated by ADAM-10. Serial deletions revealed that the length of the ectodomain negatively correlates with efficient intramembrane proteolysis. Bri3 (Itm2c), which is highly homologous to Bri2, fails to be shed. Failure of shedding of Bri3 is accompanied by a lack of intramembrane proteolysis by SPPL2b. Surprisingly, a low molecular weight membraneretained stub of Bri3 also fails to be processed by SPPL2b, indicating that shedding per se is not sufficient for subsequent intramembrane proteolysis. Extensive domain swapping analysis reveals that primary sequence determinants within the intracellular domain and the transmembrane domain together with short luminal juxtamembrane sequences are required for efficient intramembrane proteolysis.