Biomedical Engineering Reference
In-Depth Information
(Petaja-Repo et al.
2001
), and the olfatory receptors (Kato and Touhara
2009
; Lu
et al.
2003
), whose efficiency of outward trafficking is considerably less that com-
plete. Thus, the possibility that intracellularly retained misfolded or incompletely
mature receptors may be rescued from ER trapping and degradation by pharmaco-
logical interventions additionally represents an important therapeutic target for
restoration of biological function in trafficking disease.
This chapter focus on the use of pharmacoperones as an approach to rescue
function of misfolded GPCRs. Special emphasis is placed on misfolded hGnRHRs,
which have proved to represent a valuable model for the development of pharma-
coperone drugs potentially applicable to treat diseases caused by other GPCRs
misrouting.
14.2
The Endoplasmic Reticulum Quality Control System
Synthesis, folding, assembling, and processing of proteins occur in the ER and the
Golgi apparatus (Fig.
14.1a
). As any newly synthesized protein, GPCRs are
subjected to a strict quality control system (QCS) that checks the integrity and cor-
rectness of folding of the protein into a three-dimensional protein structure, which,
in principle, is determined by its amino acid sequence. Adequate folding is not
only necessary for proper function but also for trafficking of the protein to other
compartments of the cell (e.g. the plasma membrane). By monitoring the structural
correctness of newly synthesized proteins, the QCS prevents accumulation of defec-
tive, misfolded proteins that may accumulate, aggregate and interfere with cell
function. Proteins that pass the scrutiny of the QCS (i.e. correctly folded), are
allowed to continue to their final destination within the cell after processing at the
Golgi is completed (Ulloa-Aguirre et al.
2004a
). In this setting, it is understandable
why mutations yielding protein sequence variations may result in misfolded (and
disease-causing) proteins. Protein folding is, of necessity, a complex process given
the proximity and diversity of thousands of proteins that accumulate in a crowded
cytosolic environment and because the steric character of the nascent protein back-
bone restricts the configurations recognized by the stringent QCS. In this complex
scenario, the ER QCS needs to operate at several levels, employing a variety of
mechanisms that include a complex sorting system that identifies and separates pro-
teins according to their maturations status, as well as the action of specialized folding
factors, escort proteins, retention factors, enzymes and members of the molecular
chaperone families, which belong to the so-called proteostasis network (Hartl et al.
2011
; Hutt et al.
2009
; Ron and Walter
2007
). Molecular chaperones are key acces-
sory components of the ER QCS that participate co- and post-translationally in the
folding process of newly synthesized proteins (Brooks
1999
; Hartl and Hayer-Hartl
2002
; Morello et al. et al.
2000a
). They are an important control mechanism that
recognizes, retains, and targets misfolded proteins that have adopted non-native
conformations for their eventual degradation via the polyubiquitination/proteasome
pathway, preventing aggregation and accumulation of abnormal and potentially
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