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Ig superfamily proteins have similar roles in vertebrates.Proteins of the Sidekickssubfamily, for example, mediate homophilic adhesion,and different Sidekicks proteins are expressedin different layers of the retina,with synapsesforming between sets of retinal neurons that share expression ofthe same family member. \Alhenthe pattern of expression of the proteins is artificially altered, the pattern of synaptic connections changes accordingly.These Ig superfamily members are by no means the only adhesionmolecules involved in initiating synapse formation.
Misexpression of certainother synaptic adhesion proteins, unrelated to any of the types we have mentioned so far, can even trick growth cones into synapsing on non-neuronal cellsthat would never normally be innervated. Thus, if non-neuronal cells are forcedto express neuroligin, a transmembrane protein evolutionarily related to thefibronectintype lll domainsNCAM1148Chapter19:cell Junctions,cell Adhesion,and the ExtracellularMatrixenz]frJ].eacetylcholinesterase,neurons will synapse on them, as a consequenceof binding of neuroligin to a protein called neurexin in the membrane of thepresynaptic neuron.ScaffoldProteinsOrganizeJunctionalComplexesTo make a synapse,the pre- and postsynaptic cells have to do more than recognize one another and adhere: they have to assemble a complex system of signalreceptors, ion channels, slmaptic vesicles,docking proteins, and other components, as described in chapter 11.
This apparatus for synaptic signaling couldnot exist without cell adhesion molecules to join the pre- and postsynapticmembranes firmly together and to help hold all the components of the signalingmachinery in their proper positions. Thus, cadherins are generally present, concentrated at spots around the periphery of the synapse and within it, as well asIg superfamily members and various other types of adhesion molecules. In fact,about 20 different classical cadherins are expressedin the vertebrate nervoussystem, in different combinations in different subsetsof neurons, and it is likelythat selectivebinding of these molecules also plays a part in ensuring that neurons s).napsewith their correct partners.But how does the array of adhesion molecules recruit the other componentsof the synapse and hold them in place?scaffold proteins are thought to have acentral role here.
These intracellular molecules consist of strings of proteinbinding domains, typically including severalpDZ domains-segments about 70amino acids long that can recognize and bind the C-terminal intracellular tailsof specific transmembrane molecules (Figure rg-21). one domain of a scaffoldprotein may attach to a cell-cell adhesion protein, for example, while anotherlatches onto a ligand-gated ion channel, and yet another binds a protein thatregulates exocytosisor endocy'tosisor provides attachment to the cytoskeleton.Moreover, one molecule of scaffold protein can bind to another. In this way, thecell can assemble a mat of proteins, with all the components that are needed atthe synapse woven into its fabric (Figure ls-22). Several hundred different typesof proteins participate in this complex structure.
Mutations in synaptic scaffbldproteins alter the size and structure of synapses and can have severe consequences for the function of the nervous system.Among other things, such mutations can damage the molecular machinery underlying learning and memory,which depend on the ability of electrical activity to leave a long-lasting trace inthe form of alterations of synaptic architecture.The scaffold proteins, with their many potential binding partners, areinvolved in organizing other structures and functions beside synapses andsynaptic signaling.The Dlscs large (Dlg) protein of Drosophilais an example (seeFigure 19-2r). Dlg is needed for the construction of normal synapses;but weshall see that it, along with a set of other related scaffold proteins, ilso plays anneuroliging l u t a m a t er e c e p t o r s( N M D Ar e c e p t o r s )posrsynamembranedomainso t h e r s c a f f o l da n dscaffold-associatedproteinsDlg4 (PSD95)scaffoldproteinsFigurel9-21 A scaffoldprotein.Thediagramshowsthe domainstructureofDlg4,a mammalianhomologof theDrosophilaprotein Discs-large,along withsomeof its bindingpartners.Dlg4isconcentratedbeneaththe postsynapticmembraneat synapses,and is alsoknownas postsynapticdensityprotein95,or PSD95.With its multipleproteinbindingdomains,it can linktogetherdifferentcomponentsof the synapse.One moleculeof Dlg4can alsobind toanotheror to scaffoldingmoleculesofothertypes,therebycreatinganextensiveframeworkthat holdstogetherall the componentsof the synapse.Scaffoldproteinsalsohaveimportantrolesat othertypesof celljunctions.1149CADHERINSAND CELL-CELLADHESION,Utv e s i c l e - d o cnkgiproternsynaptrcvesrclest.\/ voltage-gatedC a 2 *c h a n n e lpresynaptrcmembraneposlsynapilcmembrane \ion channel(c)essential part in almost every aspect of the organization of epithelia, includingthe formation of occluding junctions between the cells, the control of cell polarity, and even the control of cell proliferation.
All these processeshave a shareddependence on the same machinery, not only in flies, but also in vertebrates.SummaryIn epithelia, as well as in some other typesof tissue,cells are directly attached to oneanother through strong cell-cell adhesions,mediated by transmembraneproteins thatare anchored intracellularly to the cytoskeleton.At adherensjunctions, the anchorageis to actin filaments; at desmosomejunctions, it is to intermediatefllaments. In boththesestructures,and in many lessconspicuouscell-cell junctions, the adhesiuetransmembrane proteins are members of the cadherin superfamily.
Cadherins generallybind to one another homophilically: the head of one cadherin molecule binds to thehead of a similar cadherin on an oppositecell. This selectiui4tenablesmixed populations of cells of dffirent types to sort out from one another according to the specificcadherins they express,and it helps to control cell rearrangementsduring deuelopment, where many dffirent cadherins are expressedin complex, changing patterns.Changesin cadherin expressioncan causecellsto undergo transitions between& cohesiueepithelialstateand a detachedmesenchymalstate-a phenomenonimportant incanceras well as in embryonic deuelopment.The "classical"cadherins are linked to the actin cytoskeletonby intracellular proteins called catenins Theseform an enchoring complex on the intracellular tail of theFigure 19-22 Organizationof a synapse.(A)Electronmicrographand (B)linedrawingof a crosssectionof two nerveon a dendritein theterminalssynapsingmammalianbrain.Notethe synapticin the two nerveterminalsandvesiclesmaterialassociatedthe dark-stainingwith the pre-and postsynaptic(C)Schematicdiagrammembranes.showingsomeof the synapticat thesecomoonentsthat areassembledsites.Cell-celladhesionmolecules,c a d h e r i nasn d n e u r o l i g i nasn dincludinghold the pre-and postsynapticneurexins,together.Scaffoldingmembranesproteinshelpto form a mat(correspondingto the dark-stainingmaterialseenin (A))that linkstheadhesionmoleculesby their intracellulartailsto the componentsof the synapticsuchasmachinery,signal-transmissionion channelsand neurotransmitterreceptors.The structureof this large,complexmultiproteinassemblyis notyet knownin detail.lt includesanchoragesitesfor hundredsof additionalnot shownhere,includingcomponents,and variousmoleculescytoskeletalregulatorykinasesand phosphatases.(A,courtesyof CedricRaine.)1 150Chapter19:CellJunctions,Cell Adhesion,and the ExtracellularMatrixcadherin molecule, and are inuolued not only in physical anchorage but also in thegenesisof intracellular signals.
Conuersely,intracellular signals can regulate the formation of cadherin-mediatedadhesions.B-Catenin,for example,is alsoa keycomponent of the Wnt cell signaling pathway.In addition to cadherins,at least three other classesof transmembranemoleculesare also important mediators of cell-cell adhesion: selectins,immunoglobutin (Igsuperfamily members, and integrins. selectins are expressedon white blood cells,blood platelets,and endothelial cells,and they bind heterophilically to carbohydrategroups on cell surfaces.They help to trap circulating white blood cells at sitesofinflammation.
Ig-superfamily Ttroteinsalso play a part in this trapping, as well as inmany other adhesiueprocesses;some of them bind homophilically, some heterophilically.Integrins, though they mainly serueto attach cellsto the extracellular matrix, canalso mediate cell-cell adhesion by binding to the lg-superfumily members.Many different lg-superfamily members,cadherins,and other cell-cell adhesionmoleculesguide the formation of nerueconnectionsand hotd neuronal membranestogether at synapses.In these complicated structures, as well as at other types ofcell-cell junctions, intracellulqr scaffold proteins containing multiple pDZ proteinbinding domains hauean important role in holding the many dffirent adhesiueandsignaling moleculesin their proper arrangements.TIGHTJUNCTIONSANDTHEORGANIZATIONOFEPITHELIAAn epithelial sheet,with its cellsjoined side by side and standing on a basal lamina, may seem a specializedtype of structure, but it is central to the constructionof multicellular animals.
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