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

Angiotensin-converting enzyme (ACE) and the Alzheimer's disease amyloid pre cursor protein are two examples of membrane-bound proteins that are release d in a soluble form by a post-translational proteolytic cleavage event invo lving a secretase. Site-specific antibodies and matrix-assisted laser desor ption ionization-time-of-flight ('MALDI-TOF') MS have been used to map the secretase cleavage site in somatic ACE to Arg1203/Ser-1204, 24 residues pro ximal to the membrane-anchoring domain. Trypsin, which can solubilize ACE f rom the membrane, cleaves the protein at the same site. The use of structur ally related hydroxamic acid-based zinc metalloproteinase inhibitors indica te that tumour necrosis factor-alpha 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 alpha-s ecretase release of the amyloid precursor protein from a human neuronal cel l line.