Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates the low-density lipoprotein (LDL) receptor, elevating LDL cholesterol and accelerating atherosclerotic heart disease, making it a promising cardiovascular drug target. To achieve its maximal effect on the LDL receptor, PCSK9 requires autoproteolysis. After cleavage, PCSK9 retains its prodomain in the active site as a self-inhibitor. Unlike other proprotein convertases, however, this retention is permanent, inhibiting any further protease activity for the remainder of its life cycle. Such inhibition has proven a major challenge toward a complete biochemical characterization of PCSK9's proteolytic function, which could inform therapeutic approaches against its hypercholesterolemic effects. To address this challenge, we employed a cell-based, high-throughput method using a luciferase readout to evaluate the single-turnover PCSK9 proteolytic event. We combined this method with saturation mutagenesis libraries to interrogate the sequence specificities of PCSK9 cleavage and proteolysis-independent secretion. Our results highlight several key differences in sequence identity between these two steps, complement known structural data, and suggest that PCSK9 self-proteolysis is the rate-limiting step of secretion. Additionally, we found that for missense SNPs within PCSK9, alterations in both proteolysis and secretion are common. Last, we show that some SNPs allosterically modulate PCSK9's substrate sequence specificity. Our findings indicate that PCSK9 proteolysis acts as a commonly perturbed but critical switch in controlling lipid homeostasis and provide a new hope for the development of small-molecule PCSK9 inhibitors.
from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2nXi4N9
via IFTTT
Εγγραφή σε:
Σχόλια ανάρτησης (Atom)
Δημοφιλείς αναρτήσεις
-
A two-arm multicenter phase II trial of one cycle chemoselection split-dose docetaxel, cisplatin and 5-fluorouracil (TPF) induction che...
-
Abstract Purpose Overcoming the flaws of current data management conditions in head and neck oncology could enable integrated informatio...
-
Differential Evolution Optimization of the SAR Distribution for Head and Neck Hyperthermia. IEEE Trans Biomed Eng. 2016 Nov 14;: Auth...
-
This paper investigates the control and synchronization of a class of chaotic systems with switched output which is assumed to be switched b...
-
RT @ecancer_espanol : Abiraterone for metastatic, hormone sensitive, prostate cancer https://t.co/xa9jVlFrCg https://t.co/dj5XAacWCF fro...
-
Melanocyte development is orchestrated by a complex interconnecting regulatory network of genes and synergistic interactions. Piebaldism and...
-
Abstract Hepatocarcinogenesis is a multi-step process characterized by progressive cellular and molecular dedifferentiation of hepatocytes ...
-
Purpose: 18 F-fluoroestradiol (FES) PET scans measure regional estrogen binding, and 18 F-fluorodeoxyglucose (FDG) PET measures tumor glycol...
-
Publication date: 1 August 2017 Source: Cancer Letters, Volume 400 Author(s): Amr S. Abu Lila, Naoto Moriyoshi, Masakazu Fukushima, Cheng-...
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου