Title:Mechanisms of Protein Misfolding in Conformational Lung Diseases
Volume: 12
Issue: 7
Author(s): N. G. McElvaney and C. M. Greene
Affiliation:
Keywords:
Alpha-1 antitrypsin, cigarette smoke, cystic fibrosis transmembrane conductance regulator,
endoplasmic reticulum stress, protein folding, proteostasis, conformation, aggregates, protein expression, hereditary disorders, protein synthesis, folding enzymes, unfolded protein response, airway stress diseases, autophagy
Abstract: Genetic or environmentally-induced alterations in protein structure interfere with the correct folding,
assembly and trafficking of proteins. In the lung the expression of misfolded proteins can induce a variety of
pathogenetic effects. Cystic fibrosis (CF) and alpha-1 antitrypsin (AAT) deficiency are two major clinically
relevant pulmonary disorders associated with protein misfolding. Both are genetic diseases the primary causes
of which are expression of mutant alleles of the cystic fibrosis transmembrane conductance regulator (CFTR)
and SERPINA1, respectively. The most common and best studied mutant forms of CFTR and AAT are ΔF508
CFTR and the Glu342Lys mutant of AAT called ZAAT, respectively. Non-genetic mechanisms can also
damage protein structure and induce protein misfolding in the lung. Cigarette-smoke contains oxidants and
other factors that can modify a protein’s structure, and is one of the most significant environmental causes of
protein damage within the lung. Herein we describe the mechanisms controlling the folding of wild type and
mutant versions of CFTR and AAT proteins, and explore the consequences of cigarette-smoke-induced effects
on the protein folding machinery in the lung.
