Class Note for BIOC 460 at UA
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Date Created: 02/06/15
BIOC 460 spring 2008 Lecture 6 Protein Tertiary and Quaternary Structure Reading Berg Tymoczxo amp Stryer 6th ed Chapter 2 pp 4453 mm Chapter 12 pp 337338 Directory of Jmol structures of proteins mommucrmmaumasuumassesmmazumzauumuuesmuuuesbm Jmol routine some structural motifs found in proteins nttp HWWW biocneni arizona educlassesbloc462462alrilolmotlfmotlf ntm Jmol routine snoWing locations of hydrophobic and hydrophilic side chains lltt vwwvbluchem allZEIna educlassesblucllEZAEZa mulsldechalnsldechaln lltml Jmol routine as 5 different domains in one subunit of pyruyate xinase littn MNWW blucllem avlztina educlassesblnrAEZAEZa mulmutelndumalnsdumalrll him Jmol structure of myoglobin i i Jmol structures of of proteins littp MNWW bluchem avlzuna edu classesblucAEZAEZa mulalpha betaalpha beta hlml Jmul structure of hemoglobin littg Wyvvvblutherri arlmna educlassesblucAEZAEZamulhemuglublrinevvhb ntnri Key Concepts Tertlafy and quaternary structures result from folding of primary structure and secondary structural elements in 3 dimensions Tertiary structure a Most proteins tertiary structures are combinations of o helices p sheets and loops and turns 7 Larger proteins often naye multiplefolding domains 7 Folding of HZOesoluble globular proteins into their natiye structures follows some basic ruleslprinciples minimization of solventaccessible surface area burying hydrophobic groups maximization of intraprotein hydrogen bonds chirality right handed twist and connectivity ofthe polypeptide backbone Quaternary structure 7 Some proteins naye multiple polypeptide chains quaternary structure 7 Arrangement of polypeptides in multimeric proteins is generally symmetrical e Quaternary structure can play important functional roles for multlr subunit proteins especially in regulation Learning Objectives Outline 3 principles guiding folding of watersoluble globular proteins andtne generalizations about protein structure resultlngfrom those principles Relate the principles to real protein structures Explain the term ampnipatnic With an ampnipatnic protein o nelix as an example Recognize examples ribbon diagrams of such common folding motifs frequently encountered combinations of secondary structures as coiled coils of arhellcesy stacxed esheets pop elements ebarrels and p saddles Explain the term tertiary structure Definetneterms domain and subunit as they relate to protein structure Be ableto recognize different domains in a ribbon diagram of a single polypeptide chain With 2 or more domains Describe in general terms the structure oftne polypeptide chain of myoglobin Learning Objectives continued Describe the structure oftne immunoglobulin fold single domain Describe the general structure of an op barrel including wherein the structure you would expect to find nydropnobic groups and where you would expect to find polarcharged groups Describe the general structure arrangement of hydrophobic ys polar R groups of a globular protein that is embedded in a lipid bilayer membrane 7 Specifically describe nowtne primary and secondary structures of a bacterial porin relate to tnetertiary structure and function of a single porin subunit Explain the term quaternary structure of a protein and be able to describe a protein in terms lixe nomotetramer x neterodimer x etc Explain simple rotational symmetry for an oligomeric protein such as a nomodimer lixe tne Cro protein or a neterotetramer lixe nemoglobin 7 Be able to use correctly the terms Zefold Srfold etc to refer to simple rotational axes of symmetry and recognize that simple leyel of symmetry in a protein structure Tertiary Structure 3dimensional conformation of a whole polypeptide chain in its folded state includes not only positions of backbone atoms but of all the sidechain atoms as well Mostwater soluble and membrane proteins are globular compact and roughly spherical 3D structures determined by e X ra y diffraction of protein crystals or 7 NMR spectroscopy of protein in solution for proteinstnat aren t too large Every protein has a unique hree dimensional structure made up ofa variety of helices ssheets and nonregular regions which are folded in a speci c mariner 3 principles guiding folding of HZOsoluble globular proteins amp consequences of those principles Generalizations about HZDsoluble globular protein structure a minimization of solventaccessible surface area a maximization of hydrogen bondin within the protein a chiral effect 1 minimization of solventaccessible surface area burying as many nydropnobic groups as possible the most important driving force in folding of watersoluble proteins Globular protein structures generally tigntly pacxed compact units Secondary structural elements arhellces and 3 sheets often ampnipatnic e R groups on one side hydrophobic andface interior of protein 7 R groups on other side hydrophilic andface aqueous envlronment outside Jmol routine snoWing locations of hydrophobic and hydrophilic side chains httg vwwv biuclrem ai izuna educlassesbluc4BZ462a muli39siuechainsiuechain litml LEC 6 Protein Tertiary and Quaternary Structure BIOC 460 spring 2008 1 Minimizing surface burying hydrophobic side chains Amphipathic secondary structural elements Burial of hydrophobic R groups away from H20 requires at least 2 interacting secondary structural elements eg 2 a helices or a Ba B loop uses cc helix to connect 2 parallel 5 strands or 2 B sheets etc How can 2 a helices get together to bury 39 hydrophobic R groups if there39s water around them amphipathic helices used to W bury hydrophobic R groups toward a interior of protein on 1 side of helix while other side of helix interacts with H20 Berg et al Fig 244 a 2 Maximizing hydrogen bonds within the protein especially important in quotdrivingquotlstabilizing formation of secondary structures like ahelices and B sheets makes burying polar NH and CO groups of backbone in interior of protein more favorable thermodynamically polar side chains sometimes also buried if their polar groups are hydrogenbonded Polar backbone groups and side chains tend to be either in contact with water hydration OR hydrogenbonded with OTHER PROTEIN GROUPS eg in secondary structures like orhelices and 5 sheets ahelical coiled coil 2 or helices coiled around each other of a Ieucine zipper motif heptad repeat schematic diagram quothelical wheelsquot projections down helix axes b Fig 1630 39om Stryer Biochemistry 4th ed1995 Residues a and d of each strand pack tightly together to form a hydrophobic core lf residues b c and fon periphery are polar or charged the helices are amphipathic helices Note Any protein cc heliX will be amphipathic if one side of the helix is in a polar environment and the other side is in a hydrophobic environment 3 the chiral effect tendency of extended backbone structural arrangements to be right handed as a result of having all Lamino acids Consequences twist and connectivity twist a helices of Lamino acids tend to be righthanded Bconformation strands and sheets of Lamino acids tend to twist in a righthanded direction forming saddles or barrels connectivity crossovers between adjacent secondary structural elements e g in Su structure are usually righthanded 3 a m Q 2 r 7 Righthanded connection IB39m Loop between 2 strands Twisted 3 sheet St ructu ral motifs recognizable patterns of combinationsgroupings of secondary structural elements bury hydrophobic R groups in between layers elements Examples of motifs coiled coils of2 or more cr helices doc stacks of sheets Su elements 5 barrels 5 sheet foldstwists into a cylinder 5 saddles twisted 5 sheet Jmol routine some structural motifs found in proteins Some motifs have functional significance such as the helixloop helix helixturnhelix DNAbinding motiforthe EF hand calciumbinding motif Others serve only a structural role watersoluble globular protein tertiary structures Examples 1 Myoglobin Mb Jmol structure of Mb httn39lr hinrhem zri nnz quot quotquot 2M6 quot 39 quot39 39 I html binds 02 in muscle cells for storage and for intracellular transport using a heme group mostly 70 ahelical rest mostly turns amp loops at surface first highresolution crystal structure of a protein ever determined very compact structure almost no empty space inside very watersoluble 5 Pro residues 4 in turns 8 or helices designated by letters A H from N to C terminus Helices amphipathic surface sides hydrophilic R groups buried sides more hydrophobic R groups LEC 6 Protein Tertiary and Quaternary Structure BIOC 460 spring 2008 Myoglobin structure continued Myoglobin Berg et al Fig 2488 structure heme black with Distribution of Amino Acrds In Mb structure Purple Fe hydrophobic residues in yellow charged residues in blue others in white A surface view B crosssectional view showing interior of protein NOTE many charged residues on surface none in interior many hydrophobic residues in interior but also a few on surface The only polar residues inside are 2 His residues involved in binding the heme and 02 Nelson amp Cox Lehninger Principles of Biochemistry Fig 416 heme in red blue residues Leu lle Val Phe Berg et al Fig 2 49 2 Triose phosphate isomerase an 43 barrel protein 3 Protein Domains an enzyme in the glycolytic pathway Jmol structures of up proteins Domains structurally independent folding units looking like separate hh n39lr hinrhem zri rm 4 39 39 L39 4 ma hm hrml globular proteins but all part of same polypeptide chain an upa barrel parallel 8stranded Bbarrel on interior surrounded by connected in same primary structure a helices a structural motif found in many different enzymes Larger proteins often have 2 or more domains Some Bap enzymes triose phosphate isomerase and one domain of Jmol routine 4 different domains in one subunit of pyruvate kinase AR 39 39 39 1htm pyruvate kinase hh n39lIwwii hinrhem zri rm 4 39 39 L39 Troponin C a protein found in muscle rrrmi riri 392 domains 3 one Polypeptide Chain 39Garrett amp Grisham 39 39 y 3rd ed Fig 630 Nelson amp Cox Lehninger Principles of Biochemistry 4th ed Fig 419 3 protein domains continued 4 Porins example of a membrane protein u i u found in outer membranes of bacteria and the immunoglobulin fold a Bsandwrch domain in outer mitochondrial membranes a cell surface protein CD4 with 4 similar domains each in a channelmrming proteins permit passage different color of ions and small molecules across The folding motif of each of the 4 domains is the same membrane Each domain consists of2 antiparallel 5 sheets with loops between 5 I r39ggul g r schem IS NOT water strands motif the quotimmunoglobulin foldquot lipid core of membrane like a very nonpolar solvent structure of each chain of porin mainly a large B barrel big antiparaIIeIB sheet 16 strands folded into a cylinder structure sort of like an quotinside outquot water soluble protein hydrophobic residues on outer surface interacting with hydrophobic lipid core of membrane inner side of the barrel forms waterfilled channel across membrane has more hydrophilic charged and polar R groups Berg et al Fig 2 52 Water lled larger hydrophobic Berg at al39r F39Q 23950 hydrophiliuhanncl exterior LEC 6 Protein Tertiary and Quaternary Structure BIOC 460 spring 2008 Amino acid sequence of a porin StrUCture Of one SUbumt Of a baCter39al porm B strands are indicated with diagonal lines indicating direction of left side view in plane of membrane right view from periplasmic space hydrogen bonding along the 5 sheet from inside looking out through pore in outer membrane hydrophobic residues F l L M V W and Y shown in yellow Berg et al Fig 1220 N term C term l Berg et al Fig 1221 On a single strand in B conformation where are the side chains of the amino acid N t th I It t h d h b d h d hl d o e e more or ess a erna ing y rep 0 ic an y rep I ic reSI ues res39dPeS all on one s39de Alternatmg s39deS in the B strands adjacent R groups project out from sheet on opposite sides 3 reSIdues R groups on one Side 1 on the other Side Quaternary structure 4 structure Examples of quaternary structure in proteins 3dimensional relationship of the different polypeptide chains subunits in a multimeric protein the way the subunits fit together bacteriophage lambda A a and their symmetry relationships homodime only in proteins with more than one polypeptide chain proteins with Berg et all Fig 253 only one chain have no quaternary structure Cro protein from Hemoglobin a heterotetramer Terminology U132 Each polypeptide chain in a multichain protein a subunit 2 identical 3 subunits red 2 subunit protein a dimer 3 subunits trimeric protein 4 tetrameric structurally similar to 2 ldemlcal homodimer ortrimer etc identical subunits B subunits yellow heterodimer or trimer etc more than one kind of subunit chains with different amino acid sequences different subunits designated with Greek letters eg subunits of a heterodimeric protein the quotcc subunitquot and the quotB cc and 5 also very similarto structure of myoglobin both primary and tertiary structure subunitquot gene duplication of single 39 ancestral ene and subse uent NOTE This use of the Greek letters to differentiate different divergentgevolu on of q polypeptide chains in a multimeric protein has nothing to do gt f t I b with the names for the secondary structures a helix and B sequences quot 39 erequot 9 quot1 conformation genes Some protein structures have very complex quaternary arrangements 39 19quot an f ld C n5erved t 390th eg mitochondrial ATP synthase viral capsids evolution Berg et ai Fig 254 Jmol structure of hemoglobin Symmetry in quaternary structures simplest kind of symmetry rotational symmetry Individual subunits can be superimposed on other identical subunits brought into coincidence by rotation about one or more rotational axes If the required rotation 180 360 l2 protein has a 2fold axis of symmetry e g Cro repressor protein above If the rotation 120 360 l3 eg for a homotrimer the protein has a 339f ld symmetry aXis39 Twofold Threefold A Rotational symmetry in proteins Cyclic symmetry all subunits are related by rotation about a single nfold rotation axis C2 symmetry has a 2 fold axis 2 identical subunits C3 symmetry has a C c 3fold axis 3 identical subunits etc 2 3 Two types of cyclic symmetry What type of rotational axis of symmetry is apparent in the Nelson amp Cox LehningerPrincipes of hemoglobin structure above 39 39 y 4th ed Fig 4 24a LEC 6 Protein Tertiary and Quaternary Structure
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