Is there a link between proprotein convertase PC7 activity and human lipid homeostasis?

A genome-wide association study suggested that a R504H mutation in the proprotein convertase PC7 is associated with increased circulating levels of HDL and reduced triglycerides in black Africans. Our present results show that PC7 and PC7-R504H exhibit similar processing of transferrin receptor-1, proSortilin, and apolipoprotein-F. Plasma analyses revealed no change in the lipid profiles, insulin or glucose of wild type and PC7 KO mice.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1).

Elevated LDL-cholesterol (LDLc) levels are a major risk factor for cardiovascular disease and atherosclerosis. LDLc is cleared from circulation by the LDL receptor (LDLR). Proprotein convertase subtilisin/kexin 9 (PCSK9) enhances the degradation of the LDLR in endosomes/lysosomes, resulting in increased circulating LDLc.

Implication of the proprotein convertases in iron homeostasis: proprotein convertase 7 sheds human transferrin receptor 1 and furin activates hepcidin.

Unlabelled: The first seven members of the proprotein convertase (PC) family activate protein precursors by cleavage after basic residues. While PC7 has no known specific substrates, it shows redundancy with other PCs. A genome-wide association study suggested that circulating levels of shed human transferrin receptor 1 (hTfR1) are regulated by PC7.

The M2 module of the Cys-His-rich domain (CHRD) of PCSK9 protein is needed for the extracellular low-density lipoprotein receptor (LDLR) degradation pathway.

PCSK9 enhances the cellular degradation of the LDL receptor (LDLR), leading to increased plasma LDL cholesterol. This multidomain protein contains a prosegment, a catalytic domain, a hinge region, and a cysteine-histidine rich domain (CHRD) composed of three tightly packed modules named M1, M2, and M3. The CHRD is required for the activity of PCSK9, but the mechanism behind this remains obscure.

Survival post surgery for malignant pericardial effusion.

The study reviews the survival of patients with malignant pericardial effusion treated with a subxiphoid pericardial window. The medical records of 60 consecutive patients diagnosed with a malignant pericardial effusion and treated with a subxiphoid pericardial window between 1994 and 2008 were reviewed. 72% had lung cancer.

The proprotein convertase PC5/6 is protective against intestinal tumorigenesis: in vivo mouse model.

Background: The secretory basic amino acid-specific proprotein convertases (PCs) have often been associated with cancer/metastasis. By controlling the cleavage of cancer-associated proteins, PCs play key roles in multiple steps of cancer development. Most analyses of the implication of PCs in cancer/metastasis relied on the use of in vitro overexpression systems or inhibitors that can affect more than one PC.

Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration.

Unlabelled: The gene encoding the proprotein convertase subtilisin/kexin type 9 (PCSK9) is linked to familial hypercholesterolemia, as are those of the low-density lipoprotein receptor (LDLR) and apolipoprotein B. PCSK9 enhances LDLR degradation, resulting in low-density lipoprotein accumulation in plasma. To analyze the role of hepatic PCSK9, total and hepatocyte-specific knockout mice were generated.

Peptidyl substrates containing unnatural amino acid at the P'1 position are potent inhibitors of prohormone convertases.

In order to study further the importance of the P'1 residue upon the activity of human PC1 and human furin, two important members of subtilisin/kexin family of enzymes, we have prepared by solid-phase Fmoc or recently introduced FastMoc chemistry a series of 10 peptidyl substrate analogs. The structures of these analogs are based upon the core sequence of pro-mPC1(83-93) namely, D-Tyr-Lys-Glu-Arg-Ser-Lys-Arg-Xaa-Val-Gln-Lys-Asp, where D-Tyr replaces the native L-Tyr residue and Xaa, representing the P'1 position, corresponds to L-Ser or to nonproteinacous amino acids such as Tle, Sarc, MLeu, Aib, D-Tic or L-Tic. Two more analogs with L-Tic at P'1 position but with one amino acid less, namely P5 Glu or P'3 Gln, and one with a Cit residue in place of Arg at P1 site of the dodecapeptide were also obtained.

Pan-neuronal mRNA expression of the secretory polypeptide 7B2.

The polypeptide 7B2 exhibits a widespread distribution in the CNS and in the endocrine tissues. By in situ hybridization in the mouse tissues, we detected 7B2-mRNA transcripts in most, if not all, neurons of the brain and spinal cord, and in the cranial and spinal ganglia. 7B2-mRNA was undetectable in supportive glial cells, ependymal cells and endothelial cells.