MM9 - Dynamic Regulation of Protein (i)

intro

cells aren't static

must change + adapt to environmental cues

growth factors stimulate cells to divide

all cellular contents (bar chromos must duplicate)

protein activity disregulation: continuous growth

ways to regulate protein activity (PTMs)

level/conc

location

ligand binding

cofactor requirements

phosphor/dephosphorylation

cleavage

e.g. in order to be functional TFs must translocate from cytosol to nucleus

high levels: more transcription + translation

Ca2+ + GTP = non-peptide moieties (can be found in different molecules)

low levels when protein is damaged/has completed its purpose

Protein degradation

When?

normal housekeeping

damaged proteins need replacing

misfolded proteins need to be recycled before they disrupt cell processes

dynamic processes

some proteins need to be tightly regulated to control function/prevent toxic build-up

e.g. cyclins

after activation via cleavage

e.g. zymogen digestive enzymes

these processes target certain proteins (specific)

How?

lysosomal degradation

degrades imported proteins

lysosomes

membrane bound organelles

arise from ER

highly acidic (pH 4) due to proton pumps pumping H+ in

necessary for acid hydrolyses (degradative enzymes)

only active @ pH4 in case they leak out (protective mechanism)

can degrade any biological material

3 pathways into lysosome...

1) autophagy

damaged proteins get packaged into autophagosomes

membranous organelles formed from ER

key method of getting rid of dangers to cell

defect: accumulation of unwanted molecules

lysosomal storage diseases - chronic inflamm

e.g. Crohn's

e.g. Inclusion (I) cell disease

accumulation of macromolecules

reduced life expectancy

2) R-mediated endocytosis

tyrosine Rs internalise + fuse with golgi app

3) Phagocytosis

usually occurs when neutrophils present

proteasomal degradation

ubiquitin-proteasome system

degrades cytosolic proteins marked for destruction

FA modification

Ligand binding

changes protein conformation, activating it

releases inhibitory/inactive subunits

changes cell location

e.g. steroid hormones bind to hormone R

R dimerises + enters nucleus

Proteolytic cleavage

NB in zymogens/proenzymes (e.g. ACE + trypsin)

also occurs in apoptosis