Aminopeptidase A activity of the murine B-lymphocyte differentiation antigen BP-1/6C3.

Wu, Qi; Li, L; Cooper, Max D.; Pierres, Michel; Gorvel, Jean‐Pierre

doi:10.1073/pnas.88.2.676

Cited by 63 publications

(39 citation statements)

References 34 publications

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“…from the cells subjected to immunoelectrophoretic blot analysis using a polyclonal antibody raised against murine APA [23]. In the crude particulate fraction from cells transfected with wtAPA, APA existing as a disulphide-linked homodimer [7]. In contrast there was no difference in electrophoretic mobility of the C43S mutant under reducing or non-reducing conditions, with the antibody detecting a protein of 147 kDa under both conditions (Figures 2A and 2B, lane 3).…”

Section: Expression and Enzymic Activity Of The Apa Mutantsmentioning

confidence: 88%

“…On the basis of its role in the brain renin-angiotensin system, inhibitors of APA have been reported as potential central antihypertensive agents [5]. APA is identical with the murine B-lymphocyte differentiation antigen BP-1\6C3 and is likely to be involved in early B-cell development [6][7][8]. Plasma APA activity is significantly and consistently lower in Alzheimer's-disease patients than in age-matched controls, and thus the enzyme may have potential use as a diagnostic\predictive marker for this disease [9].…”

Section: Introductionmentioning

confidence: 99%

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The C-terminal domain, but not the interchain disulphide, is required for the activity and intracellular trafficking of aminopeptidase A

Ofner¹,

Hooper²

2002

Biochem. J.

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Section: Expression and Enzymic Activity Of The Apa Mutantsmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

The C-terminal domain, but not the interchain disulphide, is required for the activity and intracellular trafficking of aminopeptidase A

Ofner¹,

Hooper²

2002

Biochem. J.

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“…APA has a single transmembrane-spanning domain. 42 APA can be solubilized and retains activity when clipped from the membrane by mild enzymatic digestion, 41 much like what has been shown for ACE. 43 It is not known whether plasma APA is generated in such a fashion or whether it represents a secreted form or some other APA-like enzyme.…”

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confidence: 99%

Kidney Aminopeptidase A and Hypertension, Part I

Healy

Song

1999

Hypertension

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Abstract-Tissue and plasma levels of aminopeptidase A (APA), the principal enzyme that hydrolyzes angiotensin II (Ang II) to angiotensin III, were measured in spontaneously hypertensive rats (SHR) and their normotensive control strain at 3 different ages corresponding to prehypertensive (4 weeks), developing (8 weeks), and established (16 weeks) phases of hypertension. Plasma APA activity was significantly but modestly elevated in SHR at all 3 ages compared with normotensive Wistar-Kyoto rats. Likewise, levels of APA in brain, heart, and adrenal gland were generally, but again only moderately, elevated in SHR at all ages. However, a large increase in APA activity was seen within the kidney in which APA levels were elevated 41%, 51%, and 68% in SHR at 4, 8, and 16 weeks of age, respectively. Kidney APA levels were also significantly increased in immunoblots from 8-and 16-week-old SHR. Glomeruli isolated from 16-week-old SHR had 57% higher APA activity and increased immunoreactivity compared with Wistar-Kyoto rats. To determine whether the increase in kidney APA activity in SHR was related to Ang II levels, SHR were treated for 2 weeks with the angiotensin-converting enzyme inhibitor captopril. Captopril treatment reduced blood pressure to normotensive values and resulted in a 25% reduction in kidney APA activity. These results suggest that APA expression in the kidney may be regulated by activity of the renin-angiotensin system. If so, this would further suggest that upregulation of APA during conditions in which Ang II levels were elevated would have a protective effect against Ang II-mediated cardiovascular diseases, whereas a decrease in APA expression or a failure to upregulate would exacerbate such conditions. (Hypertension. 1999;33:740-745.)

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“…This motif has been shown to be critical for both zinc binding and catalytic activity in a number of metallopeptidases, including thermolysin, a neutral protease from Bacillus thermoproteolytics, and neutral endopeptidase (11)(12)(13). Enzymatic analysis revealed that the BP-1 antigen exhibited aminopeptidase A (APA) activity (14). In addition, APA activity of a panel of cell lines correlated in a linear fashion with cell surface levels of the BP-1 antigen (14).…”

mentioning

confidence: 99%

“…Enzymatic analysis revealed that the BP-1 antigen exhibited aminopeptidase A (APA) activity (14). In addition, APA activity of a panel of cell lines correlated in a linear fashion with cell surface levels of the BP-1 antigen (14).To obtain direct evidence that BP-1 is APA, we made a full-length BP-1 cDNA clone from two overlapping partial clones. This full-length cDNA was placed downstream from the SRa promoter (15) and expressed in heterologous COS-7 and Ltk-cells.…”

mentioning

confidence: 99%

Histidine residue in the zinc-binding motif of aminopeptidase A is critical for enzymatic activity.

Wang

Cooper

1993

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

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The murine BP-1 antigen (also called 6C3) is a homodimeric, phosphorylated cell surface glycoprotein that is expressed on immature B-lineage cells, bone marrow stromal cell lines, thymic cortical epithelial cells, endothelial cells, enterocytes, and renal proximal tubular cells. The amino acid sequence deduced from a BP-1 cDNA predicted a type II integral membrane protein with a zinc-binding motif (His-GluXaa-Xaa-His) found in zinc-dependent metallopeptidases, and functional analysis suggested that BP-1 is aminopeptidase A [APA; L-a-aspartyl(L-ar-glutamyl)-peptide hydrolase, EC 3.4.11.71. Here we constructed an expression vector in which the BP-1 cDNA was placed downstream from the SRa promoter and used this construct to transfect COS-7 and Ltkcells. Both transfectants expressed the BP-1 antigen on the cell surface and APA activity. The enzymatic activity of recombinant APA was increased by Ca2+ and inhibited by Zn2+, consistent with previous reports with purified APA. Point mutation of one of the histidine residues in the zinc-binding motif to phenylalanine completely abolished APA enzymatic activity, suggesting the structure of the zinc-binding motif of APA is critical for catalytic activity. Both wild-type and mutant BP-1 were glycosylated, transported to the cell surface, and possessed molecular weights similar to native BP-1 molecules on the murine 18.81 pre-B-cell line. The successful expression of both wild-type and mutant APA should allow more precise analysis of the diverse physiological roles of this ectoenzyme.The differentiation of B cells requires interaction of lymphocyte precursors with other cell types in the microenvironments of fetal liver and adult bone marrow. Cell surface proteins expressed by developing B-lymphocyte precursors are thought to be involved in this highly complex, regulated process. The BP-1 antigen was identified as a homodimeric, phosphorylated cell surface glycoprotein on pre-B-cells and newly formed B cells in mouse bone marrow (1-3). This molecule, independently identified as a pre-B-cell neoplasiaassociated antigen and named 6C3 in another laboratory (4), is also expressed on certain bone marrow stromal cell lines and a subpopulation of thymic cortical epithelial cells (5-7).In mice, expression of the BP-1 (6C3) antigen on bone marrow-derived stromal cell lines correlates with their ability to support pre-B-cell growth (5). Interleukin 7 (IL-7) preferentially induces proliferation of bone marrow-derived pre-Bcells and up-regulates their expression of the BP-1 antigen (7,8), whereas its expression is extinguished in mature B lymphocytes and plasma cells (1). All of these observations suggest that the BP-1 molecule may play a crucial role in regulating growth and differentiation of early B-lineage cells.The BP-1 cDNA has been cloned recently (9), and the deduced amino acid sequence predicts a type II integral membrane protein with a zinc-binding motif-uncharged residue (Xaa)-Xaa-His-Glu-Xaa-Xaa-His-Xaa-hydrophobic residue-that is conserved among members of the zincd...

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Aminopeptidase A activity of the murine B-lymphocyte differentiation antigen BP-1/6C3.

Cited by 63 publications

References 34 publications

The C-terminal domain, but not the interchain disulphide, is required for the activity and intracellular trafficking of aminopeptidase A

The C-terminal domain, but not the interchain disulphide, is required for the activity and intracellular trafficking of aminopeptidase A

Kidney Aminopeptidase A and Hypertension, Part I

Histidine residue in the zinc-binding motif of aminopeptidase A is critical for enzymatic activity.

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