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  • Title: Pro-thyrotropin-releasing hormone processing by recombinant PC1.
    Author: Nillni EA, Friedman TC, Todd RB, Birch NP, Loh YP, Jackson IM.
    Journal: J Neurochem; 1995 Dec; 65(6):2462-72. PubMed ID: 7595540.
    Abstract:
    Pro-thyrotropin-releasing hormone (proTRH) is the precursor to thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2), the hypothalamic releasing factor that stimulates synthesis and release of thyrotropin from the pituitary gland. Five copies of the TRH progenitor sequence (Gln-His-Pro-Gly) and seven cryptic peptides are formed following posttranslational proteolytic cleavage of the 26-kDa rat proTRH precursor. The endopeptidase(s) responsible for the physiological conversion of proTRH to the TRH progenitor form is currently unknown. We examined the in vitro processing of [3H]leucine-labeled or unlabeled proTRH by partially purified recombinant PC1. Recombinant PC1 processed the 26-kDa TRH precursor by initially cleaving the prohormone after the basic amino acid at either position 153 or 159. Based on the use of our well-established antibodies, we propose that the initial cleavage gave rise to the formation of a 15-kDa N-terminal peptide (preproTRH25-152 or pre-proTRH25-158) and a 10-kDa C-terminal peptide (pre-proTRH154-255 or preproTRH160-255). Some initial cleavage occurred after amino acid 108 to generate a 16.5-kDa C-terminal peptide. The 15-kDa N-terminal intermediate was further processed to a 6-kDa peptide (prepro-TRH25-76 or preproTRH25-82) and a 3.8-kDa peptide (preproTRH83-108), whereas the 10-kDa C-terminal intermediate was processed to a 5.4-kDa peptide (prepro-TRH206-255). The optimal pH for these cleavages was 5.5. ZnCl2, EDTA, EGTA, and the omission of Ca2+ inhibited the formation of pYE27 (preproTRH25-50), one of the proTRH N-terminal products, by 48, 82, 72, and 45%, respectively. This study provides evidence, for the first time, that recombinant PC 1 enzyme can process proTRH to its predicted peptide intermediates.
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