54-PROTEOLYSIS – Dr. Block Flashcards
To what does plasminogen bind and where is it located with respect to clots?
Plasminogen binds to fibrin and fibrinogen. As the clost forms, plasminogen becomes incorporated within the clot.
Name 3 compounds that activate plasminogen. Describe them.
Tissue plasminogen activator (TPA) is the major activator for plasminogen. Damaged blood vessels synthesize TPA from the endothelial cells. TPA has several regions of interest: a finger domain similar to that in fibronectin; a region near the N-terminus homologous to plasminogen, which allows TPA to bind to fibrin clots and activate the plasminogen adhering to the clot. Finally there is a serine protease domain near the C-terminus.
Urokinase is a second activator of plasminogen. It can activate plasminogen in the absence of fibrin. The epithelial lining of renal tubules secretes urokinase. It contains a kringle domain in the N-terminus region. Streptokinase, isolated from streptococci, is not a serine kinase like urokinase and TPA. It forms a 1:1 complet with plasminogen to express the proteolytic activity.
How does TPA function?
TPA becomes active when bound to fibrin. It will cleave plasminogen into plasmin. Plasmin cleaves the clot into soluble products. Neither TPA nor plasmin remains bound to the soluble clot fragments. Alpha-2-antiprotease inhibits TPA and plasmin.
Describe the activity of urokinase.
Urokinase circulates in urine to lyse fibrin deposits in the renal tubules.
How does the method by which streptokinase functions differ from the ways that urokinase and TPA function?
Streptokinase is not a serine protease and can bind wholly to plasminogen. It can bind free-floating plasminogen in the fluid so that circulating fibrinogen and other plasminogen molecules can be activated.
Describe ubiquitination and the ATP dependent process of protein targeting involving ubiquitin.
Ubiquitin will tag short-lived or abnormal proteins for destruction by ATP-dependent processes. The carboxy-terminal glycine of ubiquitin covalently attaches to the E-amino group of lysine residues of proteins to be degraded. Several molecules of ubiquitin are required to tag a protein for degradation.
What determines the half-life of a protein in tissue? Give examples.
The half-life of a protein is determined by the amino acid at the animo-terminal end. T1/2 Amino Acid > 20 minutes MET, GLY, ALA, SER, THRE, VAL Stabilizing Residues 30 minutes ISO, GLU 10 minutes TYR, GLN Destabilizing Residues 7 minutes PRO 3 minutes LEU, PHE, ASP, LYS Highly Destabilizing Residues 2 minutes ARG
What is the means of protein targeting recognition and ATP dependent degradation of serum proteins?
….ATP independent processes play a role in degrading extracellular, membrane associated and long-lived intracellular proteins. Circulating proteins that lose a sialic acid residue at the non-reducing end of the oligosaccharide chain marks it for degradation. The liver asialo-glycoprotein receptors recognize these marked proteins. They are internalized and degraded by proteases in the lysozomes by proteases called cathepsins.
How are plasminogen activators used in therapy? What type of complication is likely to occur?
Plasminogen activators may be used in thrombolytic therapy t restore patency of coronary arteries after thrombosis. Administered soon after MI< these agents can possibly preserve the function of previously occluded myocardium and significantly reduce mortality. But, usually hemostatic plugs are often lysed along with the thrombus, resulting in diffuse hemorrhaging.
What are 4 major classes of proteolytic enzymes?
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What roles do proteases play in the pathogenic process in cancer? What role do they play in AIDS? What kinds of protease inhibitors are used for AIDS therapy?
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