Bioch: Programmed Destruction

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What is a Proteosome

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A large multi-protein complex that is involved in breakdown of damaged or unnecessary proteins

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Three steps in proteosome breakdown of proteins

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1: Receptor on "lid" recognizes multiubiquitin chain bound to target
2: Protein is unfolded and fed into proteasome
3: Polypeptide chain is degraded into small peptides and amino acids that can be recycled

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Mammals have:
? E1 enzymes?
? E2 enzymes?
? E3 proteins?

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1 E1 enzyme
30 E2 enzymes
>100 E3 proteins

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What do E3 proteins serve as in protein degradation?

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Specificity factors to bring a variety of different targets to a common structure that mediates their destruction

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Ubiquitin-Mediated Proteolysis Pathway has a role in:

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*Turnover of abnormal or damaged proteins
*Cell cycle control
*Stress response
*Peroxisome assembly
*Antigen processing
*Regulation of histone function
*Viral Infection
*Tissue degeneration
*Cell differentiation

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Neurological disorders involving accumulation of aggregates of misfolded or non-functional proteins:

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*Alzheimer's Disease
*Prion-related diseases

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Parkin

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*E3 ligase
*One of 3 mutated genes in Parkinson's Disease
*Mutations inactivating Parkin lead to accumulation of aggregates of proteins

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Lysosome

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Membrane-surrounded vesicles containing large varieties of hydrolytic enzymes capable of breaking down most biological molecules (proteases, lipases, nucleases, etc)

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Delivery of material to the lysosome occurs in 3 ways

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1: Endosomes
2: Autophagy
3: Phagocytosis

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Endosomes

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Membrane vesicles that are taken up by endocytosis. Fuse with lysosome adn deposit material for destruction

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Autophagy

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Process by which cells digest own organelles. Defective organell is surrounded by membrane-bound endoplasmic reticulum resulting in an AUTOPHAGOSOME, which fuse with lysosome and deposit organelle for degradation

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Phagocytosis

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Endocytosis on a large scale. Large particles (viruses, bacteria, dead cells) are engulfed into large vesicles which then fuse with lysosome.
*Carried out by Macrophages and Neutrophils

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Macrophages are involved in

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Phagocytosis. Engulf large particles and fuse with lysosomes

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Defective lysosomal function can lead to

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Tay-Sachs disease

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Tay-Sachs Disease

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Lack of functional lipases within lysosomes of nerve cells leads to massive lipid accumulation in these defective lysosomes, and eventual impaired nerve function.

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2 Main mechanisms by which cells in multi-cellular organisms die

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1: Necrosis
2: Apoptosis

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Necrosis

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Pathological response to acute cell injury
*Lysis of membrane - materials spill out
*Mitochondria swell and rupture
*General inflammatory response triggered

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Apoptosis

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Normal physiological response to suicide signals, or a lack of survival signals
*Chromatin condensation
*Cytoplasm shrinks without membrane rupture
*Cell contents packaged into membrane bound bodies, with functional organelles that may be engulfed and used by neighboring cells
*Epitopes on plasma membrane appear that attract phagocytes

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Functions of Apoptosis

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*Limb development: Sculpts structures
*Neuronal development: Neurons that fail to contact target apoptose
*Regulation of cell number
*A response to DNA damage or cell damage that can't be repaired
*Response to excessive proliferative signals
*Removal of virally infected cells

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Mechanism of apoptosis initiated OUTSIDE the cell

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Killer lymphocytes recognize foreign molecules displayed on surface of the cells destined to die
*They recruit intracellular adaptor proteins that aggregate procaspase molecules
*These procaspase molecules cleave and activate each other

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Apoptosis initiated INSIDE the cell

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Stressed cells are induced to release cytochrome C out of the mitochondria and into the cytoplasm where it binds to adaptor molecules and activates caspases

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Caspase Function

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*Caspases are proteases that are synthesized in the cell and maintained in their inactive form
*Upon activation, they cleave key components of the cell to initiate cell death
*They also cleave each other, resulting in synergistic activation
*Much like cells that respond to growth factors, this signal amplification step results in a unified cellular response