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Lecture

Bacterial AAA+ Protease: Activity Control and Toxic Deregulation

Description

This lecture explores the activity control and toxic deregulation of a bacterial AAA+ protease, focusing on the role of AAA+ machines in protein quality control, the modular architecture of AAA+ proteins, and the global activity control of the ClpC/ClpP protease by the adapter protein MecA. The cryo EM structures of the S. aureus MecA/ClpC/ClpP complex and the ClpC-ATPYS complex are discussed, along with the diverse activity states in the ClpC AAA2 ring. The lecture also delves into the mechanisms of ClpC activity control, the structural elements mediating ClpC/ClpP complex formation, and the potential of drug-induced activation of ClpC to create toxicity.

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Related concepts (23)

Protein aggregation

In molecular biology, protein aggregation is a phenomenon in which intrinsically-disordered or mis-folded proteins aggregate (i.e., accumulate and clump together) either intra- or extracellularly. Protein aggregates have been implicated in a wide variety of diseases known as amyloidoses, including ALS, Alzheimer's, Parkinson's and prion disease. After synthesis, proteins typically fold into a particular three-dimensional conformation that is the most thermodynamically favorable: their native state.

Proteasome

Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. Proteins are tagged for degradation with a small protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ubiquitin ligases.

Protease

A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do this by cleaving the peptide bonds within proteins by hydrolysis, a reaction where water breaks bonds. Proteases are involved in many biological functions, including digestion of ingested proteins, protein catabolism (breakdown of old proteins), and cell signaling.

Protein folding

Protein folding is the physical process where a protein chain is translated into its native three-dimensional structure, typically a "folded" conformation, by which the protein becomes biologically functional. Via an expeditious and reproducible process, a polypeptide folds into its characteristic three-dimensional structure from a random coil. Each protein exists first as an unfolded polypeptide or random coil after being translated from a sequence of mRNA into a linear chain of amino acids.

Equilibrium unfolding

In biochemistry, equilibrium unfolding is the process of unfolding a protein or RNA molecule by gradually changing its environment, such as by changing the temperature or pressure, pH, adding chemical denaturants, or applying force as with an atomic force microscope tip. If the equilibrium was maintained at all steps, the process theoretically should be reversible during equilibrium folding. Equilibrium unfolding can be used to determine the thermodynamic stability of the protein or RNA structure, i.e.

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