Neuropeptides: From Gene Regulation to Protein Processing

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-translational proteolytic cleavage event involving a secretase. Site-specific antibodies and matrixassisted laser desorption 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 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-a 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 asecretase release of the amyloid precursor protein from a human neuronal cell line.