Identification and characterization of proSAAS, a granin-like neuroendocrine peptide precursor that inhibits prohormone processing

Five novel peptides were identified in the brains of mice lacking active ca rboxypeptidase E, a neuropeptide-processing enzyme. These peptides are prod uced from a single precursor, termed proSAAS, which is present in human, mo use, and rat. ProSAAS mRNA is expressed primarily in brain and other neuroe ndocrine tissues (pituitary, adrenal, pancreas); within brain, the mRNA is broadly distributed among neurons. When expressed in AtT-20 cells, proSAAS is secreted via the regulated pathway and is also processed at paired-basic cleavage sites into smaller peptides. Overexpression of proSAAS in the AtT -20 cells substantially reduces the rate of processing of the endogenous pr ohormone proopiomelanocortin. Purified proSAAS inhibits prohormone converta se 1 activity with an IC50 of 590 nM but does not inhibit prohormone conver tase 2. Taken together, proSAAS may represent an endogenous inhibitor of pr ohormone convertase 1.