Formation of Activated 20S Proteasome

Intracellular Proteolytic Systems Recognize and Destroy misfolded or damaged proteins, unassembled polypeptide chains, and short-lived regulatory proteins. There are a number of mechanisms of protein degradation within cells. Two systems that play an important role in proteolysis resulting from cell stress are calpain proteases and the ubiquitin-proteasome pathway.

The calpains are a family of heterodimeric, calcium-activated cysteine proteases. They are composed of a common 30 kDa subunit and an isoform specific, catalytic 80 kDa subunit. The large subunit of Calpain I m-isoform) is activated by micromolar calcium levels, while Calpain II (m-isoform) requires millimolar levels of calcium for activation. Cell stress or injury can lead to sustained elevation of intracellular calcium levels, causing sustained activation of calpains. The common, late-stage of the cell death pathway induced by excitotoxic compounds in the nervous system involves calpain-mediated proteolysis. The ubiquitin-proteasome pathway functions widely in intracellular protein turnover. It plays a central role in degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen processing and presentation. The pathway employs an enzymatic cascade by which multiple ubiquitin molecules are covalently attached to the protein substrate. The polyubiquitin modification marks the protein for destruction and directs it to the 26S proteasome complex for degradation.

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