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 carboxypeptidase E, a neuropeptide-processing enzyme. These peptides are produced from a single precursor, termed proSAAS, which is present in human, mouse, and rat. ProSAAS mRNA is expressed primarily in brain and other neuroendocrine 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 prohormone proopiomelanocortin. Purified proSAAS inhibits prohormone convertase 1 activity with an IC(50) of 590 nM but does not inhibit prohormone convertase 2. Taken together, proSAAS may represent an endogenous inhibitor of prohormone convertase 1.
Fricker
L D
LD
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA. fricker@aecom.yu.edu
McKinzie
A A
AA
Sun
J
J
Curran
E
E
Qian
Y
Y
Yan
L
L
Patterson
S D
SD
Courchesne
P L
PL
Richards
B
B
Levin
N
N
Mzhavia
N
N
Devi
L A
LA
Douglass
J
J
D000311:Adrenal Glands / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D043423:Carboxypeptidase H; D002268:Carboxypeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007700:Kinetics; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009928:Organ Specificity; D010179:Pancreas / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D009479:Neuropeptides; C403532:PCSK1N protein, human; D011498:Protein Precursors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D011333:Pro-Opiomelanocortin; D002268:Carboxypeptidases; D043423:Carboxypeptidase H