H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 94
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(Left ) The molecular model isbased on the x-ray crystal structure of theextracellular region of v3 integrin in itsinactive, low-affinity (“bent”) form, withthe subunit in shades of blue and the subunit in shades of red. The major ligandbinding sites are at the tip of the moleculewhere the propeller domain (dark blue)and A domain (dark red) interact. An RGDpeptide ligand is shown in yellow.(Right ) Activation of integrins is thought tobe due to conformational changes thatinclude straightening of the molecule, keymovements near the propeller and Adomains, which increases the affinity forligands, and separation of the cytoplasmicdomains, resulting in altered interactionswith adapter proteins.
See text for furtherdiscussion. [Adapted from M. Arnaout et al.,2002, Curr. Opin. Cell Biol. 14:641, andR. O. Hynes, 2002, Cell 110:673.]226CHAPTER 6 • Integrating Cells into Tissuescould then alter the cytoskeleton and activate or inhibit intracellular signaling pathways. Conversely, changes in themetabolic state of the cells (e.g., changes in the platelet cytoskeleton that accompany platelet activation; see Figure19-5) could cause intracellular adapters to bind to the tails orto dissociate from them and thus force the tails to either separate or associate.
As a consequence, the integrin would either bend (inactivate) or straighten (activate), therebyaltering its interaction with the ECM or other cells.Platelet function provides a good example of howcell–matrix interactions are modulated by controlling integrin binding activity. In its basal state, the IIb3 integrinpresent on the plasma membranes of platelets normallycannot bind tightly to its protein ligands (e.g., fibrinogen,fibronectin), all of which participate in the formation of ablood clot, because it is in the inactive (bent) conformation.The binding of a platelet to collagen or thrombin in a forming clot induces from the cytoplasm an activating conformational change in IIb3 integrin that permits it to tightlybind clotting proteins and participate in clot formation. Persons with genetic defects in the 3 integrin subunit are proneto excessive bleeding, attesting to the role of this integrin inthe formation of blood clots.The attachment of cells to ECM components can also bemodulated by altering the number of integrin molecules exposed on the cell surface.
The 41 integrin, which is foundon many hematopoietic cells (precursors of red and whiteblood cells), offers an example of this regulatory mechanism.For these hematopoietic cells to proliferate and differentiate, they must be attached to fibronectin synthesized by supportive (“stromal”) cells in the bone marrow. The 41integrin on hematopoietic cells binds to a Glu-Ile-Leu-AspVal (EILDV) sequence in fibronectin, thereby anchoring thecells to the matrix.
This integrin also binds to a sequence in aCAM called vascular CAM-1 (VCAM-1), which is presenton stromal cells of the bone marrow. Thus hematopoieticcells directly contact the stromal cells, as well as attach to thematrix. Late in their differentiation, hematopoietic cells decrease their expression of 41 integrin; the resulting reduction in the number of 41 integrin molecules on the cellsurface is thought to allow mature blood cells to detach fromthe matrix and stromal cells in the bone marrow and subsequently enter the circulation.Molecular Connections Between the ECMand Cytoskeleton Are Defectivein Muscular DystrophyThe importance of the adhesion receptor–mediatedlinkage between ECM components and the cytoskeleton is highlighted by a set of hereditarymuscle-wasting diseases, collectively called muscular dystrophies. Duchenne muscular dystrophy (DMD), the most common type, is a sex-linked disorder, affecting 1 in 3300 boys,that results in cardiac or respiratory failure in the late teensor early twenties.
The first clue to understanding the molecular basis of this disease came from the discovery that persons with DMD carry mutations in the gene encoding aprotein named dystrophin. This very large protein was foundto be a cytosolic adapter protein, binding to actin filamentsand to an adhesion receptor called dystroglycan. ❚Dystroglycan is synthesized as a large glycoprotein precursor that is proteolytically cleaved into two subunits. The subunit is a peripheral membrane protein, and the subunit is a transmembrane protein whose extracellular domainassociates with the subunit (Figure 6-29). Multiple Olinked oligosaccharides are attached covalently to side-chainhydroxyl groups of serine and threonine residues in the subunit. These O-linked oligosaccharides bind to variousbasal lamina components, including the multiadhesive matrix protein laminin and the proteoglycans perlecan andAgrinNeurexinLamininPerlecanBasal laminaα,β-DystroglycanαO-linked sugarSarcoglycan complexN-linked sugarSarcospanγα β δβGRB2CytosolinrophDystSyntrophinsNOSActinα-Dystrobrevin▲ FIGURE 6-29 Schematic model of the dystrophinglycoprotein complex (DGC) in skeletal muscle cells.
TheDGC comprises three subcomplexes: the , dystroglycansubcomplex; the sarcoglycan/sarcospan subcomplex of integralmembrane proteins; and the cytosolic adapter subcomplexcomprising dystrophin, other adapter proteins, and signalingmolecules. Through its O-linked sugars, -dystroglycan binds tocomponents of the basal lamina, such as laminin. Dystrophin—the protein defective in Duchenne muscular dystrophy—links-dystroglycan to the actin cytoskeleton, and -dystrobrevinlinks dystrophin to the sarcoglycan/sarcospan subcomplex.
Nitricoxide synthase (NOS) produces nitric oxide, a gaseous signalingmolecule, and GRB2 is a component of signaling pathwaysactivated by certain cell-surface receptors (Chapter 14). See textfor further discussion. [Adapted from S. J. Winder, 2001, TrendsBiochem. Sci. 26:118, and D. E. Michele and K. P. Campbell, 2003, J.
Biol.Chem.]6.5 • Adhesive Interactions and Nonepithelial Cellsagrin. The neurexins, a family of adhesion molecules expressed by neurons, also are bound by the subunit.The transmembrane segment of the dystroglycan subunit associates with a complex of integral membrane proteins; its cytosolic domain binds dystrophin and otheradapter proteins, as well as various intracellular signalingproteins. The resulting large, heterogeneous assemblage, thedystrophin glycoprotein complex (DGC), links the extracellular matrix to the cytoskeleton and signaling pathwayswithin muscle cells (see Figure 6-29). For instance, the signaling enzyme nitric oxide synthase (NOS) is associatedthrough syntrophin with the cytosolic dystrophin subcomplex in skeletal muscle.
The rise in intracellular Ca2 duringmuscle contraction activates NOS to produce nitric oxide(NO), which diffuses into smooth muscle cells surroundingnearby blood vessels. By a signaling pathway described inChapter 13, NO promotes smooth muscle relaxation, leading to a local rise in the flow of blood supplying nutrientsand oxygen to the skeletal muscle.Mutations in dystrophin, other DGC components,laminin, or enzymes that add the O-linked sugars to dystroglycan disrupt the DGC-mediated link between the exteriorand the interior of muscle cells and cause muscular dystrophies.
In addition, dystroglycan mutations have been shownto greatly reduce the clustering of acetylcholine receptors onmuscle cells at the neuromuscular junctions (Chapter 7),which also is dependent on the basal lamina proteins lamininand agrin. These and possibly other effects of DGC defectsapparently lead to a cumulative weakening of the mechanicalstability of muscle cells as they undergo contraction and relaxation, resulting in deterioration of the cells and musculardystrophy.Ca2-Independent Cell–Cell Adhesion in Neuronaland Other Tissues Is Mediated by CAMsin the Immunoglobulin SuperfamilyNumerous transmembrane proteins characterized by thepresence of multiple immunoglobulin domains (repeats) intheir extracellular regions constitute the Ig superfamily ofCAMs, or IgCAMs.
The Ig domain is a common proteinmotif, containing 70–110 residues, that was first identified inantibodies, the antigen-binding immunoglobulins. Thehuman, D. melanogaster, and C. elegans genomes includeabout 765, 150, and 64 genes, respectively, that encode proteins containing Ig domains. Immunoglobin domains arefound in a wide variety of cell-surface proteins including Tcell receptors produced by lymphocytes and many proteinsthat take part in adhesive interactions. Among the IgCAMsare neural CAMs; intercellular CAMs (ICAMs), which function in the movement of leukocytes into tissues; and junction adhesion molecules (JAMs), which are present in tightjunctions.As their name implies, neural CAMs are of particular importance in neural tissues. One type, the NCAMs, primarily227mediate homophilic interactions. First expressed during morphogenesis, NCAMs play an important role in the differentiation of muscle, glial, and nerve cells.
Their role in celladhesion has been directly demonstrated by the inhibitionof adhesion with anti-NCAM antibodies. Numerous NCAMisoforms, encoded by a single gene, are generated by alternative mRNA splicing and by differences in glycosylation.Other neural CAMs (e.g., L1-CAM) are encoded by differentgenes. In humans, mutations in different parts of theL1-CAM gene cause various neuropathologies (e.g., mentalretardation, congenital hydrocephalus, and spasticity).An NCAM comprises an extracellular region with five Igrepeats and two fibronectin type III repeats, a single membrane-spanning segment, and a cytosolic segment that interacts with the cytoskeleton (see Figure 6-2).
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