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1007 Protein Processing Dr Rosevear
UC MED 2015 1007 Protein Processing Dr Rosevear
25
Medical
Graduate
10/07/2011

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Term
What do enzymes that are targeted to the lysosome contain?
Definition
N-linked oligosaccharide containing a terminal mannose-6-phosphate
Term
What do enzymes in the lysosome do?
Definition
Degrade carbohydrates, proteins and lipids
Term
What happens in I-Cell disease?
Definition
Hydrolytic enzymes are unable to enter into the lysosome
Term
How are M6P tags added to proteins that need to get to lysosome?
Definition
N-acetyl-glucosamine (GlcNAc) phosphotransferase recognizes only lysosomal proteins. Another enzyme removes GlcNAc leaving M6P residue on lysosomal protein. The protein is then destined for the lysosome
Term
What is the purpose of M6P receptor?
Definition
To ensure lysosomal enzymes targeted to vesicles that are ultimately directed to the lysosome
Term
Where is the M6P receptor located on the Golgi?
Definition
lumenal face of the trans Golgi
Term
How are lysosomal enzymes localized to the lysosome?
Definition
M6PR binds M6P of protein and directs it to lysosome. Membrane regions containing the receptor and its bound lysosomal enzyme pinch off to become specialized vesicles that transport the enzymes to acidic (pH = 5.0) sorting vesicles.
The low pH of the clathrin sorting vesicles causes the phosphorylated enzyme to dissociate from its receptor, and the receptor recycles back to the Golgi. The phosphorylated enzyme then loses its phosphate group and is transported to a lysosome.
The sorting of lysosomal enzymes from secretory proteins thus occurs in the trans Golgi, and these two classes of proteins are found in different vesicles that bud from the Golgi.
Term
Why is M6P receptor also found on cell surface?
Definition
To mediates the endocytosis of extracellular phosphorylated lysosomal enzymes that are occasionally
secreted and causes them to be transported to a sorting
vesicle and then to a lysosome.
Term
Biochemical basis of I-cell disease
Definition
Inclusion bodies accumulate b/c at least 8 lysosomal hydrolases are missing.
There's a missing or defective N-acetylglucosamine phosphotransferase.
An individual with I-cell disease secretes lysosomal acid hydrolases rather than targeting them to the lysosomes. The secreted hydrolases find their way to the blood. A ten- to twenty-fold elevation of hexosaminidase, iduronate sulfatase, and aryl sulfatase A activity in serum is diagnostic of I-cell disease.
Term
What are inclusion bodies
Definition
enlarged lysosomes filled with undigested material (primarily glycolipids and glycosaminoglycans)
Term
Proinsulin biosynthetic pathway
Definition
Preproinsulin undergoes 2 cleavages to become active form. C domain is cut out, leaving A and B domains. 6 insulin molecules bind to Zn to form Zn-insulin crystals. Once they pass through the plasma membrane they dissociate back into monomers
Term
Diffusion of different forms of Insulin
Definition
Monomer >> Dimer > Hexamer
Term
Lispro
Definition
Insulin analog. Reversal of 2 residues in primary sequence near the end of the B-chain decreases the tendency of insulin to form dimers and hexamers. This leads to a fast acting insulin.
The sequence inversion leads to local conformational changes which eliminate 2 critical hydrophobic interactions and weaken 2 terminal β-sheet hydrogen bonds that stabilize the dimer.
Term
Structure of insulin
Definition
51 amino acid, dual-chain hormone that is secreted and stored in pancreatic β-cells. Forms dimers at concentrations used for pharmaceutical formulations.
In the presence of zinc ions, dimers assemble into hexamers (trimer of dimers).Hexamers can adopt different conformations (T6, T3R3f, and R6).
T and R states associated with ligand binding to 2 allosteric binding sites (phenolic pocket and the His B10 Zn2+ anion site)
Term
Ultralente Insulin
Definition
Insulin analog. ultralente crystals bind methylparaben slowing dissolution of crystals and contributing to the long duration of action. Stabilizes the hexameric form, increasing its effective duration because that isn’t the active form
Term
Insulin T to R conversion
Definition
T to R transition involves a conformational change in the first nine residues of the B-chain. Three distinct conformational states: T6, T3R3, R6
These residues go from an extended conformation in the T-state to an
α-helical conformation in the R-state
Term
Difference between R and Rf state
Definition
f stands for frayed. in frayed, the last few residues of helix have coil structure
Term
Difference in anion binding site between T and R form
Definition
In T state, anion bind site is exposed to solvent. In R state, it is in a deep cavity away from solvent, allowing ligand binding
Term
How methylparaben binds to insulin
Definition
Methylparaben can bind to the insulin hexamer in both the T3R3 and R6 conformations. In the T3R3 conformation MPO binds in the phenolic pocket created by the movement of Phe B1. In the T6 conformation MPO binds at dimer-dimer interfaces of the T6 hexamer via interacting amino acids Leu A13, Tyr A14, Glu A17
Term
Philadelphia chromosome
Definition
A shortened chromosome 22 resulting from the translocation between chromosome 9 and chromosome 22. Produces BCR-ABL oncogene (chimeric protein, its presence is indicative of the disease)
Term
BCL-ABL
Definition
BCL-ABL is hallmark of all chronic myeloid leukemia (CML) and a subset of acute lymphocytic leukemia (ALL): Fusion protein between BCL and ABL. Abnormal protein molecule causes bone marrow to release large numbers of white blood cells.
BCL =breakpoint cluster gene
ABL =Abelson murine leukemia virus proto-oncogene

c-Abl functions in a range of cellular processes, including regulation of cell growth and survival, oxidative stress and DNA-damage responses, and actin dynamics and cell migration.
Term
Role of ABL
Definition
- c-Abl functions in a range of cellular processes, including regulation of cell growth and survival, oxidative stress and DNA-damage responses, and actin dynamics and cell migration.

- This constitutively activates tyrosine kinase in ABL and unleashes the ABL transforming potential leading to CML

- Normally need other cellular factors to activate ABL tyrosine kinase and cell division

- Small molecule inhibitor imatinib mesylate (Gleevec) that binds to the ABL kinase domain and inhibits the kinase

- Emergence of imatinib resistant BCR-ABL in CML patients has called for development of additional inhibitors.
Term
Mechanism of Gleevec
Definition
Normally, the substrate is activated by the phosphorylation of one of its tyrosine residues. It can then activate other downstream effector molecules.
When Gleevec in the kinase pocket, the action of BCR-ABL is inhibited, preventing phosphorylation of its substrate.
Term
How gleevec causes cancer cell death
Definition
ABL contains 3 nuclear localization signals (NLS) that shuttles the ABL protein between the cytoplasm and the nucleus in proliferating cells.

BCL-ABL contains the 3 NLS signals, but BCR-ABL located exclusively to the cytoplasm.

In the cytoplasm BCL-ABL show oncogenic activity, in the nucleus BCL-ABL can induce cell death

KINASE ACTIVITY of BCL_ABL INHIBITS ITS NUCLEAR IMPORT

Total of 9 Tyr residues in the ABL portion of BCL-ABL that can be autophosphorylated

Imatinib(Gleevec) inhibits the kinase domain and allows nuclear import of BCL-ABL via the NLS signals
Term
Very brief summary of Gleevec mechanism
Definition
Tyrosine kinase autophosphorylates ABL inducing a conformational change that prevents the NLS sites from importing the protein into the nucleus

- Imatinib (Gleevec) inhibits tyrosine kinase activity allowing the protein to be imported into the nucleus
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