Proteins misfolded

Neither chemical nor pharmacological chaperones lead to wild-type expression levels of the mutant proteins at the cell surface. Alternative or additional strategies are needed to improve the intracellular transport of the mutant proteins. In the future, dtugs may also be developed that influence those components of the quality control system that are involed in the retention of misfolded proteins. 

The UPS also plays a major role in protein quality control. In a process known as endoplasmic associated degradation (ERAD), misfolded proteins, which are formed in the endoplasmatic reticulum, are translocated back to the cytoplasm and degraded by the proteasome. 

Purification of biopharmaceuticals often involves the removal of materials with physical characteristics very similar to the desired product, such as failure sequences from DNA synthesis or misfolded proteins from bacterial fermentations. The contaminants, however, may have biological characteristics very different from the desired product, including different antigenicities, bioactivities, and specificities. There are even systems in which the... 

Reif B, Narayanan S (2007) Characterization of Interactions Between Misfolding Proteins and Molecular Chaperones by NMR Spectroscopy. 272 117-168 Reiher M, see Herrmann C (2007) 268 85-132 Renaud P, see Darmency V (2006) 263 71-106... 

The corrector activity of 15 was not limited to recombinant systems as it was confirmed in cultured HBE cells isolated from F508del homozygous patients. After 48-h incubation with 6.7 pM 15, a 2-fold increase in forskolin-stimulated chloride current (compared to DMSO-treated cells) or 14% of the response obtained in non-CF-HBE was observed. It was also reported that 14 and 15 increase the cell surface density of other trafficking-deficient proteins, including G601S-hERG. The authors speculate that this class of compounds may act on the folding pathway shared by both misfolded proteins rather than on CFTR itself [16]. 

Calcium ion release from the ER and the accumulation of misfolded proteins in the ER can trigger necrosis, and... 

There is now a growing interest in proteomic studies of brain synapses. Recent studies have revealed a high molecular complexity in the pre- and postsynaptic areas, with thousands of proteins [6]. An important investigation for the future is to identify posttranslational modifications, miscoded as well as misfolded proteins, likely to have an impact on different aspects of synaptic function as a response to the environment as well as to the lifestyle. The first challenge is to identify and quantify the presence and variation of different proteins in key structures of the pre- and postsynaptic areas in order to relate protein structures to synaptic function. Recently, a new model has been presented describing the molecular complexity of the synapse with important aspects in emotions, thinking, memory, and consciousness [7] (Fig. 17.2). 

Recently, imino sugars have found application as active site specific chaperones (ASSC) for the treatment of lysosomial storage disorders.65 An ASSC is a small molecule that bind the catalytic domain of an enzyme inducing the regeneration of the active conformation of misfolded proteins. 

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... 

Recognition of misfolding proteins by PA700, the regulatory sub-complex of the 26S proteasome. J. Biol. Chem. 

Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP (2003) The deacetylase HDAC6 regulates aggresome formation and cell viabihty in response to misfolded protein stress. Cell 115 727-738... 

---