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Lecture

Chaperones, Quality Control, and Turnover

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Department
Biology
Course
BIOLOGY 2D03
Professor
Laura Parker
Semester
Fall

Description
Chaperones, Quality Control, and Turnover Molecular Chaperones • Protein that binds a non-native conformation of another protein and by controlled binding and release, facilitates it correct fate • Prevent incorrect interactions within and between non-native polypeptides • Increase yield but not the rate of folding reactions • Differ from folding catalysts, which actually accelerate intrinsically slow steps in the folding of proteins • Binding to substrate polypeptides is reversible and dependent on ATP hydrolysis Turnover • Degradation occurs continuously over the lifetime of the cell (whether dividing or not) • Best known pathways  lysosomal and ubiquitin-mediated • Regulation  activity of hydrolysis catalyzing enzymes must be tightly regulated • 2 general strategies for regulation o compartmentalization o selective activation • lifespan of a molecule  half-life Lipid degradation • The division between degradation and remodeling is indistinct  individual lipids can be rapidly remodeled through simple reactions • Glycerophospholipids o Some degraded in lysosomes o Remodeling is the more likely fate  Both fatty acyl chains and headgroups can be exchanged for another  Also important in signal transduction • Phingolipids o Degradation and remodeling is centralized in the cell o Degraded to ceramide predominantly in lysosomes o Sugar resides removed sequentially by lysosomal glycosidases • Cholesterol o Turnover is completely different than the other 2 major classes of lipids o Cells cannot degrade o Levels are determines bu a complex balance of andogenous synthesis, uptake of extracellular cholesterol, and efflux of intracellular to vascular fluids Protein degradation • Functions o Disposal of abnormal protins o Metabolic ctrl o Cell differentiation and development o Cell cycle and proliferation ctrl o Antigen presentation • Characteristics o Turnover is extensive o Degradation of most proteins appears to be random o Individual proteins, even within the same organelle, turnover at very different rates o Key regulatory proteins have very short half-lives, or are degraded specifically at a given point in the cell cycle o Intrinsic rate of degradation of a protein is determined at 2 levels  Global properties (size, charge, flexibility, hydrophobicity, folding & assembly)  Specific sequence or structural motfs (degradation signals) o Rates can be altered by increasing the activity of a degradation pathway or by exposing a degradation motif Degradation by proteasomes • Soluble proteolytic systems in the cytosol and nucleus that degrade most short-lived proteins. • Two forms: o 20S o 26S • Two complexes that make up the proteasome o The core (20S) o The cap (19S) • The different catalytics subunits of the 20S proteasome cleave peptide bonds carboxy-terminal to basic, hydrophobic, and acidic amino acid residues. • The 26S particle seems to degrade proteins tagged with ubiquitin in an ATP- dependent manner • Ubiquitin  a highly conserved, ubiquitous protein of 76 AA o Is reversibly joined to other proteins in a series of rxns • 3 classes enzymes required for ubiquitination (E1, E2, E3) • E1 activates ubiquitin, and activated ubiquitin is then conjugated to one of the E2 enzymes • Ubiquitin is transferred to a substrate protein conjunction with an E3 proteins (ubiquitin ligase). E3 is required for the recognition of substrates. • The C-terminal glycine residue of ubiquitin forms an isopeptide bond with the ε-amino group of lysines in target proteins • A specific lysine in ubiquitin (Lys48) can then serve as an acceptor for another ubiquitin to generate multiubiquinated substrates. • Motifs that specify ubiquitination o The N-end rule  Some AA at the N-terminal were found to be destabilizing (Phe, Leu, Trp, Tyr, Arg, Lys, His)  One class of E3 enzymes might recognize these destabilizing N-termini and allow ubiquitination and subsequent degradation  Few cytosolic or nuclear proteins have desta
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