Protein processing mechanisms: from angiotensin-converting enzyme to Alzheimer's disease

Angiotensin-converting enzyme (ACE) and the Alzheimer's disease amyloid precursor protein are two examples of membrane-bound proteins that are released in a soluble form by a post-trans-lational proteolytic cleavage event involving a secretase. Site-specific antibodies and matrix-assisted laser desorption ionization-time-of-flight (‘MALDI-TOF’) MS have been used to map the secretase cleavage site in somatic ACE to Arg-1203/Ser-1204, 24 residues proximal to the membrane-anchoring domain. Trypsin, which can solubilize ACE from the membrane, cleaves the protein at the same site. The use of structurally related hydroxamic acid-based zinc metalloproteinase inhibitors indicate that tumour necrosis factor-α convertase, a member of the ADAMs (‘a disintegrin and metalloproteinase’) family of proteins, is not involved in the proteolytic release of ACE, or in the constitutive or regulated α-secretase release of the amyloid precursor protein from a human neuronal cell line.