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From page 41... ...
The hardy cells that pioneered life were remarkably self-sufficient, capable of building their own walls and membranes, re-creating their own DNA, manufacturing their own proteins. But one necessity -- the energy needed to power essential chemical reactions -- could not be generated by even the most industrious and had to come from outside sources.
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From page 42... ...
This invention -- biologists call it "respiration" -- not only protected vulnerable cellular constituents from oxygen toxicity but also enabled its inventors to realize a significant improvement in energy efficiency. So some lived on geochemicals, some on sunlight.
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From page 43... ...
For solutions to these problems, eukaryotes turned to a tried-and-true faculty: the gift of speech, embodied in the chemical language of receptors and kinases.
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From page 44... ...
44 THE LANGUAGE OF LIFE A Prokaryote (e.g., bacteria) Flagella Outer membrane or cell wall Cell membrane Golgi apparatus Cytoskeleton DNA Nucleus B DNA Eukaryote (e.g., human liver cell)
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From page 45... ...
BUILD ITAND THEY WILL TALK 45 FROM THE GROUND UP I turn on my cell phone and instead of "Welcome," the screen announces "Holla! " Ordered to erase the welcome message "cant' knock the hustle," my older daughter Jennifer has substituted this.
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From page 46... ...
Existing options just wouldnt' do; they needed new kinds of signaling molecules, sturdy enough to survive a trip from one part of the body to the other. For animal cells the freedom to embrace also established a new forum for discussion.
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From page 47... ...
Cells, whether prokaryote or eukaryote, had to navigate the same capricious environment, face the same challenges collecting and disseminating information. The availability of resources and the presence of danger, the quality of life and the actions of neighbors, still had to be encoded in a form understandable to genes and proteins, still had to be transferred across an impermeable plasma membrane, still had to be delivered to targets that organized responses.
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From page 48... ...
Working from the ground up, cells extended and updated this library of fundamental design elements to adapt the chemical language of life to meet their growing needs. New signals, new substrates, new patterns, new combinations enhanced language skills, but the real differences between the language spoken by eukaryotic cells and the language of their prokaryotic counterparts lay in the scope not the structure of that language, in the breadth and elegance of the vocabulary, and the intricacy of sentences, rather than in the wholesale redesign of fundamental mechanisms.
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From page 49... ...
"A diseased condition" of the adrenal glands, for example -- now known as Addisons' disease, after the English physician Thomas Addison, who published the first description of the condition in 1855 -- disrupted cardiovascular function, digestion, and appearance: "The leading and characteristic features of the morbid states to which I would direct attention are anaemia, general languor and debility, remarkable feebleness of the heart's action, irritability of the stomach, and a peculiar change of color of the skin .
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From page 50... ...
But one, prepared from the adrenal glands, had triggered a spectacular constriction of the artery. Didnt' the professor agree that this might mean the extract contained one of the glandular secretions so keenly sought by scientists?
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From page 51... ...
But hormones (following the purification of adrenaline, chemists also isolated cortisol, the missing factor in Addisons' disease, from the adrenal glands, as well as thyroxine from the thyroid gland, estrogen and progesterone and testosterone from the gonads, insulin and secretin from the pancreas) represented only one of the many new types of words that animal cells added to their vocabularies.
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From page 52... ...
Biodiversity -- the mosaic of life forms populating an ecosystem -- confers the resilience that enables that system to respond to a variety of environmental challenges. A diversity of signaling molecules provided evolving eukaryotic organisms a similar flexibility to meet the challenges posed by new internal contingencies.
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From page 53... ...
Diphtheria antiserum neutralized the poisonous secretions of diphtheria bacteria because it recognized a structural feature peculiar to that toxin; in the body, cells fell victim to bacterial assault because they also contained a feature -- Ehrlich called it a "side chain" -- that matched a
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From page 54... ...
Fighting and fleeing are high-energy activities, fueled by the breakdown of glucose. Running out during an emergency could be catastrophic; fortunately, the liver maintains a reserve supply, harvested from the bloodstream in times of plenty and stored in polymer form as glycogen as well as an enzyme, glycogen phosphorylase, able to
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From page 55... ...
Along with colleague Theodore Rall, Sutherland discovered that liver cells could be ground to a pulp without compromising adrenalines' ability to activate glycogen phosphorylase. In fact, Sutherland and Rall found that they could spin the slurry in a centrifuge to separate receptor and enzyme entirely (glycogen phosphorylase, a cytoplasmic protein, floated in the fluid portion at the top, while the membrane fragments containing the receptor settled to the bottom)
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From page 56... ...
This hardy molecule, Sutherland learned, was a nucleotide -- an amalgamation of a sugar, a nitrogen-spiked moiety or "base,"and phosphoric acid -- related to the ATP (adenosine triphosphate) cells relied on to power chemical reactions but bent into a ring and decorated with a single phosphate group instead of three, a structure reflected in its chemical name: "cyclic-3, 5-adenosine monophosphate," or "cyclic AMP" for short.
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From page 57... ...
In fact, by 1969 so many scientists had become interested in such receptors that it seemed as if "half the world at the time was studying cyclic AMP," recalls biochemist Robert Lefkowitz. The investigators supervising Lefkowitzs' postdoctoral research at the time, biochemists Ira Pastan and Robert Roth, were part of the wave.
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From page 58... ...
Extrapolating from the specificity of his dyes and antitoxins, Ehrlich argued that it ought to be possible to identify chemical agents with a similar specificity for pathogens, "substances which have an affinity to the cells of the parasites and a power of killing them greater than the damage such substances cause to the organism itself, so that the destruction of the parasites will be possible without seriously hurting the organism." He called the concept "chemotherapy" and demonstrated its legitimacy with his discovery of the arsenic derivative arsphenamine, or Salvarsan, the first man-made anti-infective agent. Following the same line of reasoning, physiologists-turneddrug-prospectors panned for drugs that would bind to the "side chains" recognized by endogenous signaling molecules, replicating or blocking their action.
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From page 59... ...
Nonetheless, by 1982, Bob Lefkowitz and his co-workers had corralled the 2-adrenergic receptor; by the end of the decade, they had purified 1- and -adrenergic receptors as well -- proof that receptor subtypes were actually distinct proteins, not experimental artifacts. Once theyd cloned the gene for the 2-receptor and deduced ' something of its internal structure, it was not difficult to see why the protein had been so recalcitrant either -- it was woven into the very fabric of the plasma membrane.
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From page 60... ...
Earl Sutherland discovered adrenaline's intracellular surrogate. Bob Lefkowitz put its receptors on display.
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From page 61... ...
Using the peptide hormone glucagon to stimulate adenylyl cyclase in liver cells, Rodbell decided to warm up with a few standard-issue experiments -- radioligand binding studies with radioactive glucagon, assays to measure the output of cyclic AMP at different hormone concentrations -- that should have been a mere formality. They werent.
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From page 62... ...
The transducer Rodbell discovered interceding for glucagon, subsequently christened "Gs" because it stimulates adenylyl cyclase, was, in fact, only the first of what has proven to be an extended family of such G proteins. Another, Gi, inhibits the production of cyclic AMP.
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From page 63... ...
The parent strain, a common laboratory cell line known as S49, suffered from what toxicologists would call an "idiosyncratic drug reaction" -- exposed to the rush of cyclic AMP generated by adrenergic drugs like isoproterenol, they died in their dishes. The mutant variety of S49 cell survived.
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From page 64... ...
The problem was at the level of the G protein; as a consequence, Gilman and colleague Elliot Ross reasoned, they should be able to determine if a protein isolated from normal cell membranes was, in fact, the sought-after G protein by introducing it into mutant S49 cells, treating the cultures with isoproterenol to increase cyclic AMP, and seeing if the cells lived or died. "What was needed was to rejoin the missing link," he explains.
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From page 65... ...
It's an abbreviation for "G proteincoupled receptor," one of the names researchers have given the -adrenergic receptor, the glucagon receptor, the ACTH receptor, and all the others that communicate through a G protein transducer. You could also call them "7TMRs," for "seven transmembrane receptors"; if you dont' like abbreviations, call them "heptahelical receptors," or "serpentine receptors," for the way they flow sinuously across the plasma membrane.
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From page 66... ...
GTP-activated G then stimulates adenylyl cyclase, increasing the generation of cyclic AMP, while the G duo goes its own way and speaks to other signaling relays. coupled receptor family have the same seven-helix, membrane-spanning structure.
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From page 67... ...
SNAP TO IT If cells were editors, theyd point out that the complete sentence, as ' spoken by the adrenal gland to the liver cell, goes like this: "adrenaline -- -adrenergic receptor -- Gs -- adenylyl cyclase -- cAMP -- cyclic AMP protein kinase (or "PKA"; heading the relay between receptor and target, it's the first protein to heed cyclic AMP's call) -- phosphorylase kinase (Sutherland's kinase, it's phosphorylated and activated by PKA)
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From page 68... ...
Variously called linker, adaptor, or scaffolding proteins, the new connectors were mortar and magnet to eukaryotic cells, bridging the gaps between signaling elements, preventing errors that could lead to catastrophic misunderstandings, and conserving genetic resources by increasing the versatility of the proteins they connected. Imagine you've just finished painting the living room, and now it's time to fold up the drop cloth you put down to protect the carpet.
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From page 69... ...
Conflicts would have been inevitable if not for the fact that in each protein the domain also recognized a unique configuration of amino acids flanking the consensus sequence, a second binding site responsible for choosing the one best match from the pool of potential partners. But even if promiscuity was forbidden, a protein could practice polygamy by adding more interaction domains, allowing it to bond simultaneously with several well-chosen consorts.
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From page 70... ...
Not just because its gene can also be corrupted by a tumor virus, or because an analysis of what went wrong shed light on how such viruses could turn an ordinary cellular protein into a lethal weapon, but because, in addition, Fps led Pawson to the discovery of one of the most popular interaction domains in eukaryotic signaling pathways. Pawson discovered that the Fps kinase of healthy cells (encoded by an intact gene, designated "c-fps" to differentiate it from the version damaged by the virus, designated "v-fps")
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From page 71... ...
Pawson called the dangling interaction domain "SH2," for "Srchomology 2."* The receptors for many growth factors are themselves tyrosine kinases, with a message for transcription factors that mediate the expression of genes critical to cell proliferation and maturation.
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From page 72... ...
A scaffolding protein offers a safe haven where MAP kinases can sit down and talk, passing information smoothly from first to last. Pawson compares interaction domains like SH2 and SH3 that link signaling proteins to the studs on the surface of Lego bricks.
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From page 73... ...
. The Grb2 adaptor protein binds to the phosphorylated tyrosine of the receptor by way of an SH2 interaction domain (3)
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From page 74... ...
A scheming rapscallion of a protein, -arrestin is involved in some shady goings-on with certain membrane proteins -- machinations that typically end in the receptor's abduction; surrounded, then spirited away inside the cell in a pinched-off bleb of membrane. If the receptor's lucky, it will escape with its life and eventually find its way back to the plasma membrane.
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From page 75... ...
Instead of being deported or destroyed, the -adrenergic receptor gets a new lease on life -- and the cell gains another new way to discuss matters of growth and division, without inventing a single new protein. Architect Christopher Alexander puts it simply: "Patterns," he notes, "need the context of others to make sense." Adaptor and scaffolding proteins incorporating versatile interaction domains allowed eukaryotic cells to join protein to protein and pattern to pattern, mixing and matching components to create novel pathways and larger networks.
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From page 76... ...
Eukaryotic signaling mechanisms exemplify this principle of conservation. Tried and true solutions to the fundamental problems of cell-cell communication, the basic design elements that constitute the language of life, pioneered by simple organisms, were "carried
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From page 77... ...
Like other transmembrane receptors, it comprises an extracellular binding site, a unique configuration of ridges and clefts that correspond, lock-and-key fashion, to the three-dimensional structure of the signal; a midsection submerged in the plasma membrane; and a cytoplasmic segment charged with activating an intracellular signaling relay. It always has the same seven-helical structure.
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From page 78... ...
Easily spliced into a new gene, archetypal interaction domains like SH2 and SH3 transformed ordinary proteins into versatile Lego bricks, equipped for jobs in signaling pathways as adaptors or scaffolds. Receptors and kinases continued to do the heavy lifting, while proteins fitted with these interaction domains worried about details like word order, recruiting and assembling signaling components in an approved fashion.
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From page 79... ...
Starting with walls and roofs, doors and windows; building up to houses and combining them with offices and stores; adding parks and highways, people can build a city from simple design elements. Similarly, combining signals and receptors, second messengers and G proteins, teams of kinases, adaptors and scaffolds, and linking pathways to create networks, "a few thousand gene products can control the sophisticated behaviors of many different cell types." Just as the smallest patterns help to complete the larger patterns of neighborhood and city, these smaller molecular patterns help complete complex signaling pathways that, in turn, help complete the even larger patterns of cell and organism.
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From page 80... ...
80 THE LANGUAGE OFLIFE gious displays of parental simplemindedness. "NO ONE says that anymore." Dont' worry -- they will have new words for me to learn.
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