Constitutive proteolysis

Hipkiss, A. R. (2003). Do developmental-related changes in constitutive proteolysis affect aberrant protein accumulation and generation of the aged phenotype Mech. Ageing Dev. 124, 575-579. 

In mammalian cells, the two most common forms of covalent modification are partial proteolysis and ph osphorylation. Because cells lack the ability to reunite the two portions of a protein produced by hydrolysis of a peptide bond, proteolysis constitutes an irreversible modification. By contrast, phosphorylation is a reversible modification process. The phosphorylation of proteins on seryl, threonyl, or tyrosyl residues, catalyzed by protein kinases, is thermodynamically spontaneous. Equally spontaneous is the hydrolytic removal of these phosphoryl groups by enzymes called protein phosphatases. 

Recent studies using vaginal-cervical cells suggest yet another mechanism for the early stage of tight junctional disassembly, namely, the breakdown of occludin 65-kDa isoform to the lesser functional 50-kDa isoform. Occludin appears to constitutively undergo calpain-mediated proteolysis, increasing the amount of non-functional 50-kDa isoform [35, 43], As described above,... 

Higa, L. a., Mihaylov, 1. S., Banks, D. P., Zheng, J., Zhang, H. Radiation-mediated proteolysis of CDTl by CUL4-ROC1 and CSN complexes constitutes a new checkpoint. Nat Cell Biol. 2003, 5, 1008-1015. 

Proteins can undergo different rounds of palmitoylation and depalmitoylation, either constitutively or as a response to signals." " Here the Ras proteins are the most commonly discussed examples. As described above, all Ras proteins are expressed with the CAAX-box and are subject to post-translational modifications. First, they get farnesylated and after proteolysis and methylation of the C-terminus, H-/N-Ras as well as K-Ras 4A get further palmitoylated at additional cysteines present in their C-terminus. Palmitoylation occurs in the Golgi apparatus and via vesicular transport the farnesylated and palmitoylated proteins are directed to the plasma membrane (PM). The palmitoyl thioester is hydrolyzed at multiple cellular sites and the protein is transported back to the Golgi via a nonvesicular pathway (Scheme 3)." ... 

Figure 4. Ubiquitin-mediated proteolysis regulates the onset and demise of Cdk activity during the cell division cycle. The Anaphase Promoting Complex/Cyclosome (APC/C) is active from the onset of anaphase until the end of G1 phase, during which it targets mitotic cyclins (Clbs) and other proteins such as Pdsl. The SCF complex is constitutively active but only targets Sicl and other substrates once they have been specifically phosphorylated by G1 cyclin (Cln)-Cdk (Cdc28) activity. See text for details.

The SNAREs involved in the fusion of synaptic vesicles and of secretory granules in neuroendocrine cells, referred to as neuronal SNAREs, have been intensely studied and serve as a paradigm for all SNAREs. They include syntaxin 1A and SNAP-25 at the presynaptic membrane and synaptobrevin 2 (also referred to as VAMP 2) at the vesicle membrane. Their importance for synaptic neurotransmission is documented by the fact that the block in neurotransmitter release caused by botulinum and tetanus neurotoxins is due to proteolysis of the neuronal SNAREs (Schiavo et al. 2000). Genetic deletion of these SNAREs confirmed their essential role in the last steps of neurotransmitter release. Intriguingly, analysis of chromaffin cells from KO mice lacking synaptobrevin or SNAP-25 showed that these proteins can be at least partially substituted by SNAP-23 and cellubrevin, respectively (Sorensen et al. 2003 Borisovska et al. 2005), i.e., the corresponding SNAREs involved in constitutive exocytosis. 

Additional evidence supporting the existence of two domains in apoE was obtained when apoE was subjected to limited proteolysis with a battery of five proteases having widely varying specificities (Wetterau et al., 1988). The results, summarized in Fig. 5, demonstrate that there are two protease-resistant regions in the amino-terminal (residues 20-165) and carboxyl-terminal (residues 225-299) portions of the protein, suggesting that these regions constitute the structural domains. The central portion of the protein, which is highly susceptible to proteolysis (residues 165-210), is the portion of apoE that is predicted to exist as a random structure (Fig. 2). 

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