Abstract
BackgroundAngiotensin I-converting enzyme (ACE) metabolizes a range of peptidic substrates and plays a key role in blood pressure regulation and vascular remodeling. Thus, elevated ACE levels may be associated with an increased risk for different cardiovascular or respiratory diseases. Previously, a striking familial elevation in blood ACE was explained by mutations in the ACE juxtamembrane region that enhanced the cleavage-secretion process. Recently, we found a family whose affected members had a 6-fold increase in blood ACE and a Tyr465Asp (Y465D) substitution, distal to the stalk region, in the N domain of ACE.Methodology/Principal FindingsHEK and CHO cells expressing mutant (Tyr465Asp) ACE demonstrate a 3- and 8-fold increase, respectively, in the rate of ACE shedding compared to wild-type ACE. Conformational fingerprinting of mutant ACE demonstrated dramatic changes in ACE conformation in several different epitopes of ACE. Cell ELISA carried out on CHO-ACE cells also demonstrated significant changes in local ACE conformation, particularly proximal to the stalk region. However, the cleavage site of the mutant ACE - between Arg1203 and Ser1204 - was the same as that of WT ACE. The Y465D substitution is localized in the interface of the N-domain dimer (from the crystal structure) and abolishes a hydrogen bond between Tyr465 in one monomer and Asp462 in another.Conclusions/SignificanceThe Y465D substitution results in dramatic increase in the rate of ACE shedding and is associated with significant local conformational changes in ACE. These changes could result in increased ACE dimerization and accessibility of the stalk region or the entire sACE, thus increasing the rate of cleavage by the putative ACE secretase (sheddase).
Highlights
Angiotensin I-converting enzyme (ACE, CD143) is a Zn2+ dipeptidyl carboxydipeptidase which plays a key role in the regulation of blood pressure and in the development of vascular pathology and remodeling [1,2,3,4]
The main reason for the absence of clinical abnormalities in these patients is that their tissue ACE, generally 10- to 30-fold higher than blood ACE, remains unaltered and the overall substrate hydrolysis does not change significantly
We hypothesized that the reason why most members of this family with the Y465D mutation (6 out of 7) have one or more of the above symptoms is due to elevation of plasma substance P or other neuropeptides shown to be involved in similar neuropathophysiological disorders [Nesterovitch et al 2011, in preparation]
Summary
Angiotensin I-converting enzyme (ACE, CD143) is a Zn2+ dipeptidyl carboxydipeptidase which plays a key role in the regulation of blood pressure and in the development of vascular pathology and remodeling [1,2,3,4]. Besides membrane-bound forms of ACE, blood and other biological fluids contain a variable amount of soluble ACE. Angiotensin I-converting enzyme (ACE) metabolizes a range of peptidic substrates and plays a key role in blood pressure regulation and vascular remodeling. A striking familial elevation in blood ACE was explained by mutations in the ACE juxtamembrane region that enhanced the cleavage-secretion process. We found a family whose affected members had a 6-fold increase in blood ACE and a Tyr465Asp (Y465D) substitution, distal to the stalk region, in the N domain of ACE
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