Ubiquitination

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Ubiquitination

• Ubiquitin is a small globular protein containing
  about 76 amino acids.

Attachment of ubiquitin often leads the protein
to degradation through a ubiquitin-dependent
pathway.
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Ubiquitin is linked to lysine residue of proteins
via Isopeptide bond
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Ubiquitination Reaction
Ubiquitin activation
Ubiquitin-conjugating enzyme
Ubiquitin-protein ligase
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Proteins that are targeted by UB

• Deem to be unstable proteins.
• Met, Ala in N-terminus usually stable (gt20
  hours)
• Negatively charged amino acids not stable
  (3-30 min)
• A specific sequence of amino acid residues (the
  cyclin destruction box in cell cycling proteins).
  
• Oxidative damage or other stress triggers the
  protein modification, leads to ubiquitination.

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Proteasome Degrades UB-proteins
To remove UB from protein
Degrade protein
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Ubiquitination and Cellular Process

• Gene transcription
• Cell-cycle progression
• Organ formation
• Circadian rhythms
• Inflammatory response
• Tumor progression
• Cholesterol metabolism
• Antigen processing

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Proteolytic Activation

• Zymogen, a precursor for active enzyme
• Zymogen Active enzyme
• A protective mechanism
• Activation of zymogens may be inhibited by
  specific inhibitors (regulators).

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Activation of Digestive Enzymes
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Activation of Digestive Enzymes
Hydrolyzes a unique lysine-isoleucine peptide
bond in trypsinogen
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The protease Activities Are Regulated by Specific
Inhibitors
A 6-kD protein
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The protease Activities Are Regulated by Specific
Inhibitors
a1-antitrypsin inhibitor, a 53kD protein,
inhibits elastase. Deficiency of a1-antitrypsin
results in emphysema.
M358
Methionine sulfoxide
Methionine
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Blood Clotting
Serine protease
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Fibrinogen is a Fibrin Clot Precursor
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Fibrinogen is a Fibrin Clot Precursor
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Fibrinogen is a Fibrin Clot Precursor
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Thrombosis and Hemorrhage
Thrombosis is the formation of a fibrin
clot. Hemorrhage is the loss of blood from the
circulatory system. Anti-thrombin III is an
inhibitor of thrombin and other serine
proteases in the blooding clotting. Fibrin is
eventually cleaved by plasmin, another serine
protease.