Prohormone convertase 1 (PC1) is a serine proteinase responsible for the proteolytic processing of many precursor proteins within the regulated secretory pathway. The activity of PC1 is potentially regulated by two endogenous inhibitors, the PC1 propeptide and proSAAS. Here we have investigated the effect of proSAAS and propeptide-containing constructs on PC1 carboxy-terminal processing and activity. In AtT-20 cells, proSAAS expression inhibited both C-terminal PC1 processing and proopiomelanocortin (POMC) processing under pulse/chase conditions. SAAS CT peptide-propeptide chimeric constructs had no effect on the cleavage of PC1 and POMC under pulse/chase conditions. However, a construct containing the propeptide alone reduced C-terminal PC1 processing under pulse/chase conditions and also inhibited POMC processing. In contrast, experiments using HEK293 cells transiently expressing PC1 plus the respective constructs demonstrated significant inhibition of zymogen processing and decreased C-terminal processing of PC1 by the SAAS CT peptide portion of the chimera. Our results suggest that the PC1 propeptide expressed in trans is able to act as an endogenous inhibitor of PC1, but that SAAS CT peptide-containing/propeptide constructs cannot function as effective inhibitors of precursor maturation in the regulated pathway.
SN Lee, E Prodhomme and I Lindberg
Niamh X Cawley, Guida Portela-Gomes, Hong Lou and Y Peng Loh
performed by Kex2, a subtilisin-like serine protease, it was speculated that yapsins may be backup enzymes for the serine proteases involved in prohormone processing. Mammalian aspartic proteases with similar properties to the yapsins have been characterized
Rebecca McGirr, Leonardo Guizzetti and Savita Dhanvantari
, processing and storage of peptide hormones. Peptide hormones are first synthesised as larger precursors, or prohormones, and are selectively targeted to the regulated secretory pathway via the trans -Golgi network (TGN). Proteins destined for the regulated
N M Whalley, L E Pritchard, D M Smith and A White
Introduction Like many prohormones, proglucagon is processed in a cell type-specific manner. In the α-cells of the pancreas, proglucagon is processed to glucagon by prohormone convertase 2 (PC2), but it undergoes alternative processing in the L
A Alidibbiat, C E Marriott, K T Scougall, S C Campbell, G C Huang, W M Macfarlane and J A M Shaw
pathway necessary for post-translational processing and storage of proinsulin was shown by negative prohormone convertase RT-PCR. This accounted for absent immunocytochemical staining with an antibody raised against mature insulin and undetectable insulin
Uxía Gurriarán-Rodríguez, Omar Al-Massadi, Ana Belén Crujeiras, Carlos S Mosteiro, María Amil-Diz, Daniel Beiroa, Rubén Nogueiras, Luisa María Seoane, Rosalía Gallego, Yolanda Pazos, Felipe F Casanueva and Jesús P Camiña
talk coordinates a variety of biological processes including energy metabolism, neuroendocrine function, and immune function ( Scherer et al . 2006 , Virtue & Vidal-Puig 2010 ). Added to this capacity, adipose tissue expresses a broad spectrum of
Abdullah Cim, Greta J Sawyer, Xiaohong Zhang, Haibin Su, Louise Collins, Peter Jones, Michael Antoniou, Jean-Paul Reynes, Hans-Joachim Lipps and John W Fabre
probably represents the result of a more complex transdifferentiation process. To investigate this further, the presence of other pancreatic β cell proteins was evaluated. The results in Fig. 5 demonstrate that the prohormone convertase 1/3, essential for
Deiodinases: the balance of thyroid hormone
Ana Luiza Maia, Iuri Martin Goemann, Erika L Souza Meyer and Simone Magagnin Wajner
D2), via outer (5′)-ring deiodination of the pro-hormone T 4 . Type 3 iodothyronine deiodinase (D3) catalyzes the inner (5)-ring deiodination of T 4 and T 3 , thus inactivating the thyroid hormone action. In the last decades, several studies have
S Wei, Y Feng, FY Che, H Pan, N Mzhavia, LA Devi, AA McKinzie, N Levin, WG Richards and LD Fricker
ProSAAS is a neuroendocrine peptide precursor that potently inhibits prohormone convertase 1 in vitro. To explore the function of proSAAS and its derived peptides, transgenic mice were created which express proSAAS using the beta-actin promoter. The body weight of transgenic mice was normal until approximately 10-12 weeks, and then increased 30-50% over wild-type littermates. Adult transgenic mice had a fat mass approximately twice that of wild-type mice, and fasting blood glucose levels were slightly elevated. In the pituitary, the levels of several fully processed peptides in transgenic mice were not reduced compared with wild-type mice, indicating that the proSAAS transgene did not affect prohormone convertase 1 activity in this tissue. Because the inhibitory potency of proSAAS-derived peptides towards prohormone convertase 1 is much greater in the absence of carboxypeptidase E activity, the proSAAS transgene was also expressed in carboxypeptidase E-deficient Cpe (fat/fat) mice. Although the transgenic mice were born in the expected frequency, 21 of 22 proSAAS transgenic Cpe (fat/fat) mice died between 11 and 26 weeks of age, presumably due to greatly elevated blood glucose. The levels of several pituitary peptides were significantly reduced in the proSAAS transgenic Cpe (fat/fat) mice relative to non-transgenic Cpe (fat/fat) mice, suggesting that the transgene inhibited prohormone convertase 1 in these mice. Taken together, these results are consistent with a role for proSAAS-derived peptides as neuropeptides that influence body weight independently of their function as inhibitors of prohormone convertase 1.
L Friis-Hansen, KA Lacourse, LC Samuelson and JJ Holst
The maturation of many peptide hormones is attenuated in carboxypeptidase E (CPE)-deficient fat/fat mice, leading to a slowly developing, adult-onset obesity with mild diabetes. To determine the contribution of the hormones generated from the proglucagon precursor to this phenotype, we studied the tissue-specific processing of glucagon and glucagon-like peptide-1 (GLP-1) in these mice. In all tissues examined there was a great reduction in mature amidated GLP-1. Furthermore, a lack of CPE attenuates prohormone convertase processing of proglucagon in both the pancreas and the intestine. These findings suggest that defects in proglucagon processing together with other endocrine malfunctions could contribute to the diabetic and obesity phenotype in fat/fat mice.