l-19 Proteolysis 2 - latency and activation

Objectives 1)Appreciate that some proteins are synthesized as inactive species that need to be activated by proteolytic processing by cellular proteases to perform their biological functions 2) Consider role of three different families of proteolytic enzymes in latency and activation i) Proprotein Convertases Subtilisin/Kexin (PCSKs) protein maturation receptor recycling exploitation by pathogens ii) Metalloproteinases cell surface cleavage cancer invasion iii) Secretases cell surface activation of proteins role in Alzheimer’s

When are signal peptides (pre peptides) removed

after sorting by proteolysis

where are signal peptides on the secretory proteins

at the N terminus

where does protein activation occur

In vesicles and organelles

What must be removed in order for protein activity to occur

Pro-peptides

most bioactive polypeptides must be inactive within what pathway

the secretory pathway

what do removal of pro-peptides allow for

rapid response to cellular need

cleavage sites must contain how many basic residues at least

2

Propeptides serve a variety of purposes but must be removed for what

•full activity

Most propeptides are cleaved by PCSKs at sites containing how many basic residues

2-5

Cleavage can act as what type of mechanism

post-translational control mechanism

•Targeting of LDL receptors to lysosomes- use of _________ for hypercholesterolemia

inhibitors

Why do pathogens exploit PCSKs

cell entry

give an out come for Matrix metalloproteinases act on the ECM

–Wound healing

–Tissue remodelling

–Ovulation

–Pregnancy

–Cancer metastasis

what do secretases do

liberate active domains from membrane-bound proteins

what is a potential use for secretase inhibitors

therepeutics - Alzheimers

what does BACE stand for in terms of BETA secretases

beta-site amyloid cleaving enzyme

what family is alpha secretase part of

ADAMs

what does alpha secretase possess

metalloprotease and transmembrane domains

What is ADAM17 known as

TACE

Alpha secretase is responsible for

a wide range of ‘sheddase’ activities

where is APP expressed

in both neuronal cells and extra-neuronal tissues

Role of APP

cell adhesion, migration and gene expression

Where is Ab found

Amyloid plaques

Subtilisin-related serine proteases cleave where

at basic sequences to remove propeptides

Cleavage is exploited by toxins, viruses (e.g. SARS-CoV-2)

Metalloproteinases (MMPs) act where

cell surface

Secretases play a central role in the activity

surface proteins