Chaperones model

Liautard, J.P. Analytical background and discussion of the chaperone model of prion diseases. Biotheoretica 1999, 47, 219-238. 

The model in Figure 5 includes formation of both soluble and insoluble complexes of sHsp and substrate. The formation of insoluble sHsp/substrate complexes is consistent with the in vivo transition of sHsps to an insoluble, structure-bound form under many stress conditions as discussed above. At present we can provide only speculative explanations for this insolubility in the context of the chaperone model of sHsp function. From in vitro studies, it is clear that the ability of sHsps to keep substrates soluble is dependent on the sHsp-to-substrate ratio, the rate of substrate denaturation, and other factors in vitro conditions can be manipulated to cause precipitation of sHsp and substrate, as well as to maintain substrate solubility. Thus, insolubilization could result from a type of overload of the soluble binding capacity of the sHsps. Since in vivo there is good evidence that the insolubilization is reversible, this leads to the intriguing question of the mechanism of resolubilization, and whether this is also a function of Hsp70 systems, or if additional components are required. Alternatively, sHsp insolubilization in vivo could result from interaction with insoluble components in the cell. 

The chaperone model for sHsp function provides a basic framework to explain the many proposed sHsp/protein interactions and potential functions. The diversity of the sHsp family, however, indicates that care must be taken in generalizing biochemical properties and activities across different family members. Nonetheless, we now have a firmer structural foundation on which to design future experiments to build a biochemical mechanism of action. 

FIGURE 6.36 A model for the steps involved in the folding of globular proteins. Chaperone proteins may assist in the initiation of the folding process. 

Fig. 3. Modulation of the activity of HrcA a working model. It is assumed that HrcA repressor synthesized de novo or dissociated from its operator is present in an inactive form unable to interact with its operator. Through interaction with the GroE chaperone machine, inactive HrcA is converted into its active form...

The role of chaperone proteins in the folding of proteins is presented, and a model describing budding... 

In the classic model of synaptic vesicle recycling in nerve terminals, synaptic vesicles fuse completely with the plasma membrane and the integrated vesicle proteins move away from the active zone to adjacent membrane regions (Fig. 9-9A). In these regions, clathrin-mediated synaptic vesicle endocytosis takes place rapidly after neurotransmitter release (within seconds) [64]. The process starts with the formation of a clathrin-coated pit that invaginates toward the interior of the cell and pinches off to form a clathrin-coated vesicle [83]. Coated vesicles are transient organelles that rapidly shed their coats in an ATP/chaperone dependent process. Once uncoated, the recycled vesicle fuses with a local EE for reconstitution as a synaptic vesicle. Subsequently, the recycled synaptic vesicle is filled with neurotransmitter and it returns to the release site ready for use. This may be the normal pathway when neurotransmitter release rates are modest. Clathrin/ EE-based pathways become essential when synaptic proteins have been incorporated into the presynaptic plasma membrane. 

Parkin substrates. (B) A model for Parkin-dependent degradation of misfolded proteins. Parkin recruits a complex containing molecular chaperones and the unfolded substrates to the proteasome. Degradation may be facilitated by... 

Hay, D.G., Sathasivam, K., Tobaben, S., et al. (2004) Progressive decrease in chaperone protein levels in a mouse model of Huntington s disease and induction of stress proteins as a therapeutic approach. Hum. Mol. Genet., 13, 1389-1405. 

Fig. 9.11. Model of regulation and activation of Raf kinase. The active Ras.GTP complex binds and activates Raf kinase, which passes the signal on to the MAP kinase pathway. Various proteins including the 14-3-3 proteins and the molecular chaperons hsp 90 and p50 are thought to be involved in the regulation of the Raf kinase signahng function. In addition, Raf kinase is regulated by phosphorylation. Tyr phosphorylation (possibly via Src kinase) and Ser phosphorylation via protein kinase C have a stimulatory effect. In contrast, Ser phosphorylation via protein kinase A has an inhibitory effect. RTK receptor tyrosine kinase.

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