146 Chapter3: Proteins Fur 9-26 Sen proper of hl GED atts femora: satus weoch ethers oper rar atthe porn te econ (Sheer te subunit stem athe helce hates ree tics we wots ee ante {Cond Djatnispureal ur The feoummatteop hort eect rere ti Siecy above te ht te ate fatsin (hse vader path hae or {Ghbathe same rune’ of ebuntse etn A etrcanethornght ‘nde oreunded wreck Newel oroverbe sane j tesco uch ven wneud Shakes hat funced Nowe dues wih tty tetas te oncogenes when ww" itis turned upside down. Colesgen isthe 0 abundant ofthese proteins in anima ts8Ues. A COlagE Fone 27 calagen anda molecule consist of three long polypeptide chains, each containing the non (A)colgen spe hea forned by Polar amino acid lycine a every thitd position. This egula stricture allows the the erences procan care at rep shai te whud around oneanother o generate long regular tiple nel figure weatdone aot oto Kany 3-274), Many collagen molecules then bind to one another side-by-side and fedike collagen molecules ate cross: end-to-end to create long overiappingarrays—thereby genertingthe ecremely Med pte he xoceu space tough colligen Ms that give connective issues thelr tensile suength, as [ofommunutecate clean fey deseribed in Chapter 19. ‘steel. The striping on the collagen fibril ic ‘Stvedoy te eguaepeatng Srenoetento te eione rete: ‘whine ei. En poppe aly Los et oh Sha teenage toy ‘tee case: Ca datn 1 has been well known for a long time thet, in complete contrast to collagen, TOE uncols ito armoreexterdec another abundant protein in the extracellular matrix, elastin, is formed ae & — Sncrecolsapomanecesty seston nthe highly discrdered polypeptide. This cisorder isessental for elastins function. (tS Stetening ce tla Many Proteins Contain a Surp: Unstructured Polypeptide CI <——‘THE SHAPE AND STRUCTURE OF PROTEINS ea... j m= 1 : 1 1 ¢ Four 5 Tree mechanisms o length determination fringe rola Siterbte A) Coser slang an elongaie core pot er Imociomolade that acs af measung deve. (9 Ternation of ‘aml becnie of tin tha acest he pahrere swutue 3 btn vbr ar ode 2 tht beyond acerain rth teeny ‘equiedw terete subunit ote the chan becomes excnive) ge (GA vemer tos of sembly, wich twa set oe mole ‘String lent fave sogaered corpo et ew nl ees ‘racy match The nate devs tm arnesrng device Dated onthe ‘ine penile, eosin earl insane ‘ase, « long core protein or other macromolecule provides a seaffld chat deter tines the extant ofthe final assembly. Ths isthe mechanism that determines ‘the length ofthe TMV partile sshere the HINA chain provides the core. Similarly, ‘care protein Is chought to determine the length ofthe tin Mlataents in mus cle, aswell s tho longth ofthe long tails of some bacterial viruses (Figure 3-24), Assembly Factors Often Structures the Formation of Complex Biological ‘Not all cellular stratares held together by noacovalent bonds selfassemble. A anitochondrion, a elium. or a myofibnil of a musee cel, for example, cannot {orm spontanzously from asclution ofits component mecremelecales. Ip these ceases, part of the assembly information is proviced by special enzymes and other proteins that perform the function of templates, guiding constauction but Taking no part in te final assembled structure. Even piatively simple stuetures may lack some ofthe ingredients nocessary for their own assembly. In the formation of certain becterel viruses, for exam ple, the head, which is composed of many coples of a single protein subunit. Is Assembled on a temporary scaffold composed ofa second protein, Because the Secora proce is absent from the fnal viral parce che iad stucture carn, spontancously reassemble onco it has been taken apart. Other examples are Known in ishich proteolytic cleavage is an essenticl and ireversible step in the ‘normal assembly process, This is even the case for some small protein zssem- blies including the structural protein Gla and the hormone insulin (igure 2-35), From cso relatively staple exaanples, i seems certain that he assembly fe structure as complex as a mitochondrion oF ain wil involve temporal ‘and spatial ordering imparted by numerous other cell components. Figuic3-24 An dleton micrograph of bacterephige lamba Th po! thea tal staches toa spect poten th surars of abactera cl ‘fer bich the tig packages ONAin te ends jected cus te {alintothe col. Theta ha pede lena, etre by the "eckansm shown in gure 3338, 151HOW GENOMES EVOLVE the original gene, which are arranged as a series of homologous DNA. sequences located within 50,090 nucleotide paiss of one another. & similar Cluster of a-globin genes is located on @ separate hurman chromosome. Because the d- and -giobin gene clusters are on separate chromosomes birds and mammals but see together in the frog Xenopus its bolioved that a chromosome translocation event separated the two gene clusters about S00 million years apo (see Figure 4-87) There are several duplicated globin [INA sequences in the a- and f-lobIn {gene clusters that are not functional genes but pseudogenes. These have a dose sequence sinilarityw die functional genes buthave been disabled by ssutetons ‘hat prevent dei expzession. The existence of such pseudogenes makes it clear that, ea expected, not every DNA duplication leads to a new functional gene. We also know that nonfunctional DNA sequences are not rapidly discarded, as indi- cated by the large excess of noncoding DNA that is found in mammalian genomes. Genes Encoding New Proteins Can Be Created by the Recombination of Exons ‘The role of DNA duplication in evolution is not confined to the expansion of {gone families. It ean alsa act on 2 srnaller scale to create single genes by string Ing together short duplicated segments of DNA. The proteins encoded by genes. ‘generated in this way can be recognized by the presence of repeating similar protein domains, which aze covalently linked to one another in series. The immunoglobulins (Figure 4-88) and albumins, for exaraple, as well 25 most fibrous proteins (such as collagens) are encoded by genes that have evolved by repeated duplications of primordial DNA sequence. In genes that have evolved inthis way, as well asim many other genes, exch separate exon often encodes an individual protein folding unit, or domain. HS believed that the organization of DNA coding sequences as a sertes of such ‘exons separated by Jong intcous Las greatly faciltaied the evolution of new pro~ {eins The duplications necessary to form & single gene coding fora procein with repeating domains, for example, caa often occur by breaking and rejoining the DNA anywhere in the long intions on either side af an exon; without introns there would be only few sites in she original gene at which a recombinational ‘exchange between IDNA molecules eau duplicate the domain, hy enabling the ‘duplication to ocear by recombination at many potential sites rather ian Justa ‘ew, inirons increase the probability of a favorable duplication eve. ‘Mote generals, we know from genome sequences that dhe various parts of _genes~—both their individual exons and their egulaiory elements —have served ‘os modular elements that have boon duplicatod and moved about the genome to create the great divorstyofliving things. Thus, for ecampla, many present-day proteins are formed! asa patchevert of damains from dilerere origins, rslecting ‘heir lang evolutionary history (see Figure 3-1 2 ae om e ‘ sit rece So Figure 4-88 Schematic vew ofan anvtody drmmurogiobain| molecule Thismaeauetsacomplex ftw \danteatheayy chanson gt caine Each Rew chain contains four smi covalent Inked domaine. seca tent cham contains we sch Gdrmeins Each deman's encoded oy 2 apart cn sede ofthe ors ‘rowaht fave evolved by te sors ‘pletion afasingle anestal ocrTHE BASAL LAMINA {nadjacent plasma membranes, promote cell survival, proliferation, or differen: tiation, and serve as highways fot cell migration, “The mechanical role is nevertheless essontial. Inthe ékin, for example, the epithelial outer layer—ihe epidermis—depends on the strength of the basal lamina to keep it attached to the undertying connective tssue—the dermis. In people with genetic defects in certain basal lemina praelns or m2 special ype ‘of GONE that anchors the basal lamina to the underlying connective tissue, the epidermis becomes detacted fiom the dermis. This causes a blistering dis: oe called jnetional pero bulls a severe an sometines leon ition, 1165;‘THE BASAL LAMINA in adjacent plasma membranes, promote cell survival proliferation, or diteren- tation, and serve 2s highways for cell migration, ‘Tho mechanical role is nevertheless essential. in the akin, for example, the epithelial outer layer—the epiderris—depends on the sirength of the basal lamina to Keep it attached to the underlying connective rissue—the dermis. n peuple with genetic defect in certain basal lamina proteins or ina special ype of that anchors tie basal lamina to dhe underlying connective tissue, the epidermis hecomes detached from the dermis, This eases a bilstring dis- ‘ease called junctional epidermotyss bullosa a severe and sometimmestetial con- aiton, Laminin isa Primary Component of the Basal Lamina ‘The basal lamina is synthesized by the cells on each side oft the epithelial calls contribute one set of basal lamina comparients. while cells of the underlying bed of connective tissue (called the siromua, Greek for *bedding’) contribute another set (Figure 19-40), Like other extracellular matrices in animal tissues, the basal lamina consists of ro main classes of extracellular macromolecules: (1) fibrous proteins (usually glycoproteins, which have short oligosaccharide side chains attached) and (2) polysaccharide chains of Uie type called ghcosarogtyeas| (GAGS), which are usually found covalent linked to specific core proteiasto form proteeg'ycans (Figure 19-41) In alate section, we shall discuss these two large And varied classes of matrix molecules n greater detail. We introduce them here thrvugh the special subset that are found in basal famine. Although the precise composition of the mature basal lamina varies from tissue to tissun andl even froma region to region in dhe same lamina, it typically Contains the glycoproteins Janunin, type 1V collagen, and nidogen. along, wh the proteoglycan perlecar. Together with these key components, present in the bbacal laminae of vitally all animal feom jellyfish to maramals ic holds in its meshes, or is closely associared with, various other molecules. These inelude collagen XI (an atypical member of the collagen family, forming the core pro- tein of proteoglycan) and floronectin a Mbrous protein Importantin the adie- sion of connective tissue cals to matrix. The laminin is thought to be the primary organizer of the sheet stcture, and eatly in development, basal laminae consist mainly of laminin molecules. Laminia-l (classical laminin) is large, exible protein Composed of three very nell als oa 1165, Figure 19-40 The basa lamina inthe cornea e chick embrya In ths Seanring ection mcrogagh some of the epihela cals have been teroved ‘expose the upper surface of the rake bbl lamina, A network colagen foal inthe undering connective tse Ireracts vith te ower ae fhe levine (Courtey of Robt Telit)