ex. kinase phosphorylate serine far from active site of glycogen phosphorylase, and inactivate it
acetylation
ex. histone
at lys or N-terminals
reversible
Methylation
On Arg and lys
epigenetics
irreversible?
Ubiquitination
target to proteosome degredation
lipid association
Myristoylation
amide bond links C14 lipid with protein N-terminus
Palmitoylation
thioester bonds link C16 lipid with cys residue
Reasons to regulate proteins
overcome low speed of translation
turn on/off can save energy of translation
contol activities in different compartments
Simply works
Noncovalent changes
All reversible
for molecules require to turn on/off repeatly
molecules bind to proteins
proteins
e.x. α 1-antitrypsin inhibit elastase
elastase break down elastin
together with collagen strenthen connective tissue
normally against pathogen
a lys of it binds almost irreverisbly to elastase active site(S1 pocket's Asp)
one kind of acute phase protein
normally stored in liver, effect in lungs
deficiency of the gene leads to pulmonary emphysema
smoking waken its effect by oxidize a methionine residue
emphysema
organic metabolites/signaling molecules
cAMP
cAMP act as a common secodary messenger
Receptors generate cAMP when hormones activate them
Adenyl cyclase
transmembrane protein
activated by GPCR's ATP binded Ga subunit
cAMP dependent protein kinase
Part of the regulatory subunit resembles a kinase substrate and occupies the catalytic site of catalytic subunit: like CRRC
by a pseudosubstrate sequence
cAMP binds to the regulatory subunit, weaken those interactions and release the catalytic subunit of kinases
like RR+2C
GTP binding proteins family
Ras
120 kDa
Timer
Upstream signaling protein SOS interacts with RasGDP and activates it by exchange its binding GDP into RasGTP
under the GTP binding conformation, N-terminal SH2-SH3-SH2 domains transmit signal towards down stream by interact with downstream proteins(effectors).
C-terminal GAP and other domains of Ras hydrolyisis Ras binding GTP to GDP, and inactive Ras protein from RasGTP to Ras GDP.
part of the mitogenic signal transduction pathway
Carcinogenesis
Oncogenes
regulated by Ras GTPase activating protein
Ran
ran help impoltin back to the cytoplasm
it's activated by one subunit of importin into GTP binding form
timer
Small GTPase subunit
20-40kDa
or GAP domains
GAP adds an extra residue to the Ras GTPase catalytic site
accelerate timmer
metabolites
Usually feedback inhibition
simple competative
Allosteric
ex. Aspartate transcarbamoylase
inhibited by its product CTP
small ions
Ca2+
calmodulin
Ca2+ can activate it by conformational changes of allosteric binding , and activated calmodulin can further activate other proteins, like myosin kinase
myosin kinase phosphorylates myosin light chain, which leads to musle contraction.
Ca2+ act as another common secondary messenger
Fe2+
Diphtheria toxin gene repressor
Fe2+ binding moves DNA recognition helix close together, and moves away N-terminal blockage of DNA binding
proton
PH dependent conformational changes
usually utilized by parasites(fusion protein)
Dipthria toxin
reducing PH in endsome fasilitate releasing of toxic enzymatic domain
modify ribosome
low PH changes the conformation of the fusion protein: the translocation domain
fuse with membrane and release toxic domain
degestive enzyme
acid activates pepsin
protonates active site's aspartic acid
then self cleavage
double insurance
Allosteric
binding distance from active site
lead to conformational change
Competative
direct blockage of active site
combining
Glycogen phosphorylase
active enzyme/ inactive enzyme is proportional to [AMP]/[ATP}
regulated by allosteric activation, inhibition.
and phosphylation
Changes by regulation
change proteins' interactions with other molecules
substrate
enzyme
by
1. reorganize existing active site residues
most
by allosteric conformational changes
by cleavage
e.x. chemotrypsin
2. remove/add blockage on active site
3. change on active site
Formation
NTN hydrolase self cleavage's N-terminal
Blockage
Kinase phosphorylate a serine residue around the active site of isocitrate dehydrogenase
