In hemidesmosomes, the transmembrane connector proteins are called integrins; like cadherins, these attach to intracellular intermediate filaments, and thus they functionally link the cytoskeleton to the ECM. Focal adhesion complexes are large macromolecular complexes that localize at hemidesmosomes, and include proteins that can generate intracellular signals when cells are subjected to increased shear stress, for example, endothelium in the bloodstream, or cardiac myocytes in a failing heart.
Communicating junctions (gap junctions) mediate the passage of chemical or electrical signals from one cell to another. The junction consists of a dense planar array of 1.5to 2-nm pores (called connexons) formed by hexamers of transmembrane protein connexins. These pores permit the passage of ions, nucleotides, sugars, amino acids, vitamins, and other small molecules; the permeability of the junction is rapidly reduced by lowered intracellular pH or increased intracellular calcium. Gap junctions play a critical role in cell–cell communication; in cardiac myocytes, for example, cell-to-cell calcium fluxes through gap junctions allowing the myocardium to behave as a functional syncytium capable of coordinated waves of contraction—the beating of the heart.
BiosyntheticMachinery:EndoplasmicReticulumandGolgiApparatus
The structural proteins and enzymes of the cell are constantly renewed by a balance between ongoing synthesis and intracellular degradation. The endoplasmic reticulum (ER) is the site of synthesis of all transmembrane proteins and lipids needed for the assembly of plasma membrane and cellular organelles, including the ER itself. It is also the initial site of synthesis of all molecules destined for export out of the cell. The ER is organized into a mesh-like interconnected maze of branching tubes and flattened lamellae forming a continuous sheet around a single lumen that is topologically contiguous with the extracellular environment. The ER is composed of distinct domains that are distinguished by the presence or absence of ribosomes (
Fig. 1.6
Rough ER (RER): Membrane-bound ribosomes on the cytosolic face of the RER translate mRNA into proteins that are extruded into the ER lumen or become integrated into the ER membrane. This process is directed by specific signal sequences on the N-termini of nascent proteins. Proteins insert into the ER fold and must fold properly in order to assume a functional conformation and assemble into higher order complexes. Proper folding of the extracellular domains of many proteins involves the formation of disulfide bonds. A number of inherited disorders, including many cases of familial hypercholesterolemia (Chapter 6), are cause by mutations that disrupt disulfide bond formation. In addition, N-linked oligosaccharides (sugar moieties attached to asparagine residues) are added in the ER. Chaperone molecules retain proteins in the ER until these modifications are complete and the proper conformation is achieved. If a protein fails to fold and assemble into complexes appropriately, it is retained and degraded within the ER. Moreover, excess accumulation of misfolded proteins—exceeding the capacity of the ER to edit and degrade them—leads to the ER stress response (also called the unfolded protein response or the UPR), which triggers cell death through apoptosis (Chapter 2).
As an example of the importance of the ER editing function, the disease cystic fibrosis most commonly results from misfolding of the CFTR membrane transporter protein. In cystic fibrosis, the most common mutation in the CFTR gene results in the loss of a single amino acid residue (phenylalanine 508), leading in turn to misfolding, ER retention, and degradation of the CFTR protein. The loss of CFTR function leads to abnormal epithelial chloride transport, hyperviscous bronchial secretions and recurrent airway infections (Chapter 7).