Principles of Biology contents 10 Proteinsdls.ym.edu.tw/course/hb/doc/lecture4-(10)...

contentsPrinciples of Biology

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10 Proteins

Proteins are a diverse group of polymers that play a critical role in nearly all cellfunctions.

Quinoa grains have very high protein content, much higher than that of wheat or rice grains.Protein is not only a source for human nutrition; it also composes the fundamental structural elements of a cell.Scimat/Science Source.

Topics Covered in this Module Four Levels of Protein StructureProtein Function

Major Objectives of this Module Describe the chemical structure of an amino acid.Explain the four levels of protein structure.Associate protein structure to function.


10 Proteins

Nineteenth-century scientists applied the name proteins to define the"primary" class of molecules in living things, after the Greek word proteus.Were the scientists justified in applying this authoritative label given that theylacked sophisticated technologies for biochemical analysis? Decades ofprotein research vindicated their pronouncement, which shed light on thecritical role of proteins in nearly every cell function and structure.

Four Levels of Protein StructureThe human body may contain up to several million different kinds of proteins.Why does the body need so many? Proteins are sophisticated and complexstructures. Proteins carry out most of the cell's varied life functions andcontribute to the diversity of cell structures. Table 1 summarizes therelationship between major protein functions and structure.

Structuralsignificance Major protein function

Metabolism —catalyzing chemicalreactions

Enzyme molecules are catalysts that lowerthe energy necessary for a reaction to occur,thus greatly increasing the rate of reaction.Most enzymes are proteins. These proteinscatalyze reactions by binding to reactants,which they must match perfectly. Cells needthousands of different enzymes to catalyze allof their metabolic reactions.

Signaling — deliveringchemical messagesthroughout cells andtissues of anorganism

Proteins serve as both message transmittersand receivers, linked by structure. Forexample, some neurotransmitters aremessenger molecules that are used to signalto brain cells, which contain multiple receptorproteins for different neurotransmitters. Areceptor's structure allows it to bind to aspecific neurotransmitter.

Transport — carryingmolecules into andout of cells andthroughout the body

Proteins transport nutrients, waste products,and other substances between cells, withincells, and across cell membranes. Eachtransport protein has a unique structure tobind to specific substances, just ashemoglobin in red blood cells binds to oxygento transport it throughout the body.

Structure — formingorganelles and othercell structures aswell as the basis ofmacroscopicstructures

Proteins provide structural support toorganelles, cells, and organs. Organelleproteins provide structure and carry outrelated functions. Proteins determine a cell'soverall shape and form as well as thestructure and mechanical properties oftissues and organs such as the skin.

Movement — movingsubstances, cells,and body parts

Protein structure controls contractile andmotor functions. These proteins can movesubstances within cells. Coordinatedmovements in tissue cells producemacroscopic movements of larger body parts,

Figure 1: Amino acid structure.

© 2013 Nature Education All rightsreserved.

Figure Detail

An amino acid contains an aminogroup, a side chain (R-group), acarboxyl group, and a hydrogen atomall bound to a central, alpha carbonatom.

like when muscle tissue contracts to movebone.

Defense — defendingthe body againstdisease-causingagents

Proteins in the immune system such asantibodies bind to and destroy invasivebacteria and viruses. The structure of anantibody is specific to a certain bacterium orvirus. The body builds immunity by producingnew antibodies for each new bacteria andvirus it encounters.

Table 1: Major protein functions.A protein's structure is intimately linked to its function.

At the most basic level, proteins are made up of one or more polypeptides.Polypeptides are chains of amino acids linked together by peptide bonds.How can these chains form thousands of different molecular structures? Theamino acid chains, or polypeptides, form up to four levels of structureresulting in structural and functional diversity.

Primary structure: Amino acids link together to form a linearpolypeptide.The primary structure of a protein is the linear sequence of its amino acids.An amino acid monomer (Figure 1) includes a central carbon atom, calledthe alpha (α) carbon. The alpha carbon bonds to

a hydrogen atom,1. an amino group (–NH3

+),2. a carboxyl group (–COO-) and3. a side chain or R-group.4.

Amino acids differ by the type of attached side chain. Amazingly, cells useonly 20 different types of amino acids to build virtually all of the proteinsneeded to maintain life functions (Figure 2). How does this work?

Figure 2: The 20 amino acids.

© 2011 Nature Education All rights reserved.

The amino group and the carboxyl groupare always the same, but the R-group differs in each of the 20 aminoacids. The side chain determines whether the amino acid is polar,nonpolar or electrically charged (positively or negatively).

Figure 3: Peptide bond.

© 2014 Nature Education All rights reserved.

A peptide bond is formed between the carboxyl and amino groups of twoadjacent amino acids. R1 and R2 represent the different R-groups in thispolypeptide.

In Figure 2, notice that the R-groups are categorized according to theirchemical properties. Amino acids with nonpolar R-groups are hydrophobicand tend to aggregate within the core of a protein or in the lipid portion of cellmembranes, where they are shielded from water molecules. Amino acidswith polar R-groups are hydrophilic and tend to be on the outside of aprotein, where the amino acid is in contact with the aqueous environment.R-groups that are charged can be either acidic (negative charge) or basic(positive charge) and are also hydrophilic, and each binds well to moleculesof the opposite charge. Within a protein, these amino acid R-groups caninteract with each other in various ways to create tertiary and quaternarylevels of structure. In this way, the 20 amino acids present in cells cancombine to form many thousands of proteins that each have a specificfunction.

How does the cell link amino acids together? A carboxyl group can bond withan amino group through a dehydration reaction — the removal of a watermolecule — that forms a peptide bond. A peptide bond is the covalent bondbetween carbon and nitrogen that forms after a dehydration reactionbetween two amino acids (Figure 3). Dehydration reactions link amino acidsinto polypeptide chains. Side groups, as their name suggests, stick out to thesides of the backbone. The peptide backbone consists of the nitrogen andcarbon atoms from the amino and carbonyl groups and the alpha carbons ofeach amino acid of the polypeptide. Polypeptide chains range in length froma few amino acids to more than a thousand.

Secondary structure: Hydrogen bonds between atoms in thepolypeptide backbone create a folded or coiled shape.Segments of the polypeptide chain can form coiled or folded patterns calledthe secondary structure. Hydrogen bonds between repeating atoms in thepeptide backbone produce these secondary structures, which contribute tothe overall shape of the protein. Different patterns are formed by differenthydrogen bond formations. Different segments of a polypeptide chain canform different secondary structures, although not all regions of a polypeptidecontain secondary structure.

Consider two primary types of secondary structure in detail. Looping coils

Figure 4: Secondary structures.

© 2014 Nature Education All rights reserved. Figure Detail

Hydrogen bonds between amino and carbonyl groups hold togetherstructures such as α-helices and β-pleated sheets. In the ribbon diagramof the β-sheet, the flat arrow points to the carboxyl end of the polypeptide.

called α-helices develop from the hydrogen bonds that form between theoxygen of a carbonyl group and the amino group hydrogen of the amino acidfour residues later in the chain. Folded patterns called β-pleated sheetsform when two or more strands of a polypeptide are parallel (in the same oropposite directions), and hydrogen bonds form between adjacent carbonyloxygen and amino hydrogen atoms. Hydrogen bonds that form betweenstrands in slightly different planes produce a pleated pattern. The hydrogenbonds also serve to hold the parallel strands together in a sheet-likestructure (Figure 4).

Tertiary structure: Interactions between side chains create a three-dimensional shape.Tertiary structure is the main, three-dimensional shape of a polypeptidechain. This shape results from, and is held together by, bonds andinteractions between R-groups and atoms of the peptide backbone andbetween different R-groups themselves. These bonds and interactions arehighly dependent on the chemical properties of the R-groups and include

Hydrophobic interactions — clustering of nonpolar side chains,which are hydrophobic, with each other and toward the core of theprotein in a manner that minimizes contact with water molecules inthe surrounding fluid.Hydrogen bonding — polar R-groups can form hydrogen bondswith other polar R-groups, carbonyl and amino groups in the peptidebackbone, and water molecules in the surrounding fluid.Disulfide bridges — the sulfur-containing R-group of cysteine canbind covalently with the R-group of an adjacent cysteine, formingwhat is known as a disulfide bridge between the two cysteineresidues.Ionic bonding — an ionic bridge can form between adjacentpositively and negatively charged R-groups.van der Waals forces — when nonpolar amino acids are close

© 2014 Nature Education All rights reserved. Transcript

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together, these weak electrostatic forces can add stability to thestructure.

A complex web of these interactions results from the ordering of amino acidsin a polypeptide chain, giving each polypeptide a unique tertiary structure.View Figure 5 to see an animation of how tertiary structure builds on primaryand secondary structure.

Figure 5: Primary, secondary, and tertiary structure.The interactions between the amino acids within a protein lead to theoverall structure of the protein.

It is important to remember that all of these structures depend critically onexternal environmental conditions, such as pH and temperature. Whentemperature or pH reach extremes, the hydrogen bonds essential tosecondary and tertiary structure can break down through the process ofdenaturation. As a result, a denatured protein irreversibly loses its shapeand thus its function.

Test Yourself

How does a protein's tertiary structure depend on its primary structure?

Quaternary structure: Associations of polypeptides form a functionalprotein.Many proteins contain multiple polypeptide units assembled into a functionalmacromolecule, which may include multiple copies of the same polypeptideunit, different polypeptide units, or both. These proteins have a quaternarystructure resulting from the aggregation of separate identical or differentpolypeptides, known as subunits. Quaternary structure uses the samepalette of bonds and interactions used to form tertiary structure; only thebonds and interactions occur between atoms of separate polypeptide units.

© 2012 Nature Education All rights reserved. Transcript

Hemoglobin is an oxygen-transport protein found in the red blood cells ofmost vertebrates. It is a quaternary structure of four separate polypeptidesand is therefore sometimes called a tetramer. Click on the interactive diagramin Figure 6 to investigate the levels of structure in hemoglobin.

Figure 6: Levels of structure in hemoglobin.Hemoglobin is an example of a protein with a quaternary structure.

Four Levels of Protein Structure

Protein Function

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Controlling the formation ofbacterial biofilmsAntitoxin MqsA helps mediate the bacterialgeneral stress response.

Deconstructing the plant waterfilterA novel protein family mediates Casparianstrip formation in the endodermis.

Adaptor proteins regulate cellsignalingStructural basis for regulation of the Crksignaling protein by a proline switch.

Huntingtin protein toxicity isreduced when phosphorylatedKinase inhibitors modulate huntingtin celllocalization and toxicity.

Classic paper: The discovery ofthe neutron (1932)Possible existence of a neutron.

The role of cyclin D1 in DNA repairlinked to cancer growthA function for cyclin D1 in DNA repairuncovered by protein interactome analysesin human cancers.

Classic paper: How scientists

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discovered the enzyme that turnsRNA into DNA (1970)RNA-dependent DNA polymerase in virionsof RNA tumour viruses.

Classic paper: How reversetranscriptase turns RNA into DNA(1970)RNA-dependent DNA polymerase in virionsof Rous sarcoma virus.

Prions go toxic and cause diseasePrion propagation and toxicity in vivo occurin two distinct mechanistic phases.

A new technique for detectingautoimmune diseasesAutoantigen discovery with a synthetichuman peptidome.

Classic paper: X-rays reveal thestructure of myoglobin (1958)A three-dimensional model of the myoglobinmolecule obtained by X-ray analysis.

Using E. coli to produce biofuelfrom proteinIn the search for affordable sustainablefuels, E. coli are being engineered toconvert amino acids into high qualityalcohol-based fuels.

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Know your proteins: The PDB, aninformation portal to biologicalmacromolecular structures

Solve protein puzzles and get to knowfamous proteins

Learn about research questions in proteinchemistry

Thinking about graduate school? Watch thisPBS documentary first!


10 Proteins

Figure 7: Collagen.


Collagen's molecular structure is ideal for resisting tensional stress. Itsthree polypeptide chains are twisted together like the strands of a rope.Analysis of collagen's lower structural levels reveals that this foldingpattern is further stabilized by hydrogen bonding among the threepolypeptide chains.

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Protein FunctionTable 1 provides a wide range of critical functions carried out by proteins andthe intimate link between a protein's structure and its function. Let's take acloser look at examples of protein function.

Collagen is one of the most ubiquitous proteins in the bodies of vertebrates.It plays an important role in connective tissues, including cartilage, tendons,and bone and skin tissues. Collagen is made up of three separatepolypeptides, each with a left-handed helical secondary structure. Thesethree helices are then woven into a durable right-handed triple helix (Figure7). This quaternary structure is stabilized by the hydrogen bonds that formbetween each of the three component polypeptide chains.

Test Yourself

How does the structure of collagen relate to its function?

Future perspectives.Understanding how proteins work lies at the root of understanding brainfunction. Protein receptors in brain cells receive communications from othercells in the body. Researcher Eric Gouaux and his colleagues at OregonHealth Sciences University recently completed a map of a complex and veryimportant brain receptor called the glutamate receptor. Binding of theneurotransmitter glutamate, an amino acid, to the glutamate receptor (itself aprotein macromolecule) triggers opening of an ion channel located at thebottom of the receptor. This event allows ions to flow across the neuronalmembrane, enabling transmission of an electrical impulse down the nerve.This is a fundamental property of brain and nerve function, all followingglutamate receptor activation. As a complex protein macromolecule, theglutamate receptor is composed of four subunits that form the shape of thecapital letter Y (Figure 8). The two prongs at the top of the Y shape areinvolved in receptor modulation, meaning they change how effectively the

Figure 8: Structure of the glutamate receptor.

Graphic courtesy of Lawrence Livermore National Laboratory.Figure Detail

A glutamate receptor is composed of four subunits, each shown here in adifferent color. The subunits form prong-like shapes similar to the top ofthe capital letter Y. Binding of the neurotransmitter glutamate to thereceptor at the prongs of the Y modifies the receptor's structure andcauses the ion channel at the bottom of the receptor to open (at the stemof the "Y"; opening not shown). The stem of the Y is the area of thereceptor embedded in the cell membrane.

BIOSKILL

receptor works. Below these prongs is the binding site for glutamate. Gouauxlikened the glutamate receptor-channel shape and structure to a Mayantemple. He was surprised to discover that the receptor is made up of foursubunits that are chemically identical, but folded differently. Such a discoveryis unusual. Gouaux stated, "The completely astonishing thing was that twosubunits are completely different from the other two. That difference wastotally unanticipated." Figuring out how the chemically identical subunits areeach folded differently will be the next challenge. Ultimately, resolving thisquestion and the overall structure of the glutamate receptor will allowresearchers to develop drugs to treat a variety of neurological problems inthe human brain.

X-ray Crystallography is an Important Technique in Determining ProteinStructureScientists use X-ray crystallography — a technique that measures the

Figure 9: X-ray diffraction.

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Rosalind Franklin showed DNA's helical structure with X-ray diffraction in1953. This process and image became the foundation for establishing theshape of many other biological molecules, including proteins.

angle and intensity with which X-rays are diffracted when passing through acrystalline structure to determine the structures of many biologicalmolecules. Most famously, Rosalind Franklin (1920–1958) used thistechnique in the discovery of DNA's double helix (Figure 9).

Dorothy Crowfoot Hodgkin (1910–1994), Franklin's contemporary, developedthe methodological and technological path for protein structure discovery byadvancing techniques for resolving fine details of macromolecules. Hodgkin'simportant discoveries, including the structures of penicillin, insulin, andvitamin B12, won her a Nobel Prize in 1964 and led to medical advances thatdirectly improved the health of millions. A technological pioneer inbiochemistry, she was the first person to use an electronic computer — anearly IBM — for biochemical analysis in the 1940s. She used the computerto perform calculations of X-ray output data. Hodgkin pioneered techniquesfor developing three-dimensional models of biological molecules. Today, tensof thousands of proteins have been analyzed by X-ray crystallography atangstrom (10-10 m)-level resolution. Researchers use the X-raycrystallography data to produce three-dimensional models.

First, researchers crystallize the proteins. Although softer and more flexiblethan mineral crystals, biological molecules are highly ordered and patterned.To crystallize proteins, researchers prepare a concentrated, pure solution ofthe protein sample and allow it to crystallize on a slide. Then researchersbombard the protein crystals with X-rays, which diffract when they interact

Figure 10: Comparing electron density maps with three-dimensionalribbon models.


Pay attention to the locations of the structures on the electron mapmarked by researchers and where these locations correspond to themodel. Scientists interpret the electron density map to identify thelocations of specific amino acids, such as the alanine residue labeled Ala753 in panel (a). From here, an overall structure of the entire protein canbe predicted (b).

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with atoms in the crystal. By measuring the locations of X-rays exiting thecrystal, researchers can, with a considerable amount of mathematicalcomputation, calculate a map of electron densities in the crystal. Peaks inthe electron density map correspond to the atomic positions in the molecularand intermolecular distances. From that map, researchers can construct athree-dimensional model of the molecule (Figure 10).

Test Yourself

Describe the secondary and tertiary structure of the protein in Figure 10.

BIOSKILL

Future perspectives.In the 1990s, research confirmed the existence of strange infectious proteinscalled prions. These highly unusual pathogens lack genetic material.Modified prion proteins cause fatal neurodegenerative diseases such asbovine spongiform encephalopathy (BSE, commonly called mad cowdisease) and Creutzfeldt-Jakob disease (CJD). A person can be infectedwith these diseases by ingesting brain matter that contains the infectiousproteins. Researchers have discovered that normal cellular prion protein(PrPC), which is naturally occurring in the brain, is converted structurally intothe infectious prion protein PrPSc through a process that increases itsβ-pleated sheet content. Many aspects of prions remain mysterious. Forexample, some evidence suggests that normal PrPC plays a protective rolein the maintenance of myelin nerve sheaths protecting the brain fromdeveloping the plaques associated with Alzheimer's disease. Researchersare still working to shed light on prions and their role in neurologicaldisorders.


Protein Function

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Classic paper: How scientistsdiscovered the enzyme that turnsRNA into DNA (1970)RNA-dependent DNA polymerase in virionsof RNA tumour viruses.




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10 Proteins

OBJECTIVE Describe the chemical structure of an amino acid.An amino acid is a monomer composed of a central carbon atom, or alpha(α) carbon, surrounded by an amino (–NH3

+) group, a side chain or R-group,a carboxyl (–COO-) group, and a hydrogen atom. Virtually all proteins arecomposed of just twenty different amino acids, each with a unique R-group.

OBJECTIVE Explain the four levels of protein structure.Protein structure can occur at four levels. Primary structure is the order ofamino acids linked together in a polypeptide chain. These chains can formsecondary structures, such as α-helices or β-pleated sheets held together byhydrogen bonds within the backbone. Tertiary structures emerge fromchemical bonds and interactions among R-groups and between R-groupsand atoms on the backbone. Proteins with combinations of multiplepolypeptide units have quaternary structure resulting from the aggregation ofthe tertiary structures.

OBJECTIVE Associate protein structure to function.The structure and function of proteins are inextricably linked. Proteinsperform multiple critical functions, including transport, signaling, movement,immune defense, and structural support. Each of the many thousands ofproteins in a typical organism has a unique structure related to its specificfunction.

alpha helixA secondary level of protein structure; formed by the coiling of a polypeptide heldtogether by hydrogen bonds between carbonyl oxygen and amino hydrogen atomsin the peptide backbone.

amino acidThe monomer of polypeptides; composed of a central carbon atom with an amino(–NH3

+) group, a carboxyl (–COO-) group, a hydrogen atom and a uniqueR-group.

beta pleated sheetA secondary level of protein structure; formed when one or more strands of apolypeptide align parallel to one another and hydrogen bonds between carbonyloxygen and amino hydrogen atoms in the peptide backbone form between thestrands.

catalystA substance that speeds up a reaction without itself being consumed in thereaction.

denaturationBreakdown of the secondary and tertiary structure of a protein by exposure toenvironmental stresses, making the protein non-functional.

disulfide bridgeCovalent bond formed between sulfur atoms of two cysteines; important in thetertiary and quaternary levels of protein structure.

hydrophobic effectThe clustering and grouping of the nonpolar side chains of a polypeptide tominimize contact with water molecules; important in the tertiary and quaternarylevels of protein structure.

Summary

Key Terms

peptide bondA chemical bond between carbon and nitrogen that forms when two amino acidscombine in a dehydration reaction.

polypeptideChain of amino acids linked together by peptide bonds.

primary structureThe first level of protein structure; the sequence of amino acids coded for in DNA.

proteinA biologically important type of molecule made up of one or more polypeptides;most diverse form and function of the biological macromolecule groups.

quaternary structureThe fourth level of protein structure; involves two or more polypeptides (which mayor may not be identical) that have folded into their tertiary structure(s) and interactto form a single functional unit.

secondary structureThe second level of protein structure; structure of coils and folds along the peptidebackbone due to hydrogen bonding between atoms of the peptide backbone;distinct from tertiary structure which involves interactions of R-groups.

tertiary structureThe third level of protein structure; interactions between the R-groups or betweenR-groups and the peptide backbone that contribute to the unique three-dimensional shape of a polypeptide.

x-ray crystallographyTechnique that can determine the structure of molecules, including biologicalmacromolecules, by measuring angle and intensity of diffraction of X-rays as theypass through a crystalline structure.


Protein Function

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10 Proteins

1.

α-helicesamino groupsthe overall three-dimensional shape of multiple polypeptide subunits when they arejoined togethercarboxyl groupsNone of the answers are correct.

Which of these is an example of protein secondary structure?

2.

the order of amino acids in the polypeptide chainthe formation of α-helices and β-pleated sheetsthe three-dimensional structure of multiple polypeptides into a functional proteinthe overall three-dimensional shape of a single polypeptide chainAll answers are correct.

Which best describes the quaternary structure of a protein?

3.

sending and receiving signalsdefending against pathogenstransporting nutrients across membranesstructural supportAll answers are correct.

What is the role of proteins in the body?

4.

phosphate groupamino groupcarboxyl groupR-group (or side chain)alpha-carbon

Which of the following is NOT one of the four components of all amino acids?

5.

covalent bondshydrogen bondshydrophobic effectsvan der Waals forcesAll answers are correct.

Which chemical interactions hold together secondary structures to form the three-dimensional tertiary structure of a protein?

6.

structural support in plant cell wallsenzymatic catalysis of chemical reactions by protein enzymestransporting molecules throughout an organism with transport proteinsmovement resulting from protein contractiondefense against pathogenic infections through protein antibodies

Which of the following is not a typical protein function?

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