H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 28
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Each of the distal globular domainsin HA binds sialic acid (red) on the surface oftarget cells. Like many membrane proteins,HA contains several covalently linkedcarbohydrate chains (not shown).HA2DISTAL65Neu protein, which takes part in embryonic differentiation;and Notch protein, a receptor protein in the plasma membrane that functions in developmentally important signaling(Chapter 14). Besides the EGF domain, these proteins contain domains found in other proteins.
For example, TPA possesses a trypsin domain, a common feature in enzymes thatdegrade proteins.EGFNeuEGFprecursorTPA▲ FIGURE 3-8 Schematic diagrams of various proteinsillustrating their modular nature. Epidermal growth factor(EGF) is generated by proteolytic cleavage of a precursor proteincontaining multiple EGF domains (green) and a membranespanning domain (blue). The EGF domain is also present in Neuprotein and in tissue plasminogen activator (TPA). These proteinsalso contain other widely distributed domains indicated by shapeand color. [Adapted from I. D. Campbell and P. Bork, 1993, Curr.
Opin.Struct. Biol. 3:385.]66CHAPTER 3 • Protein Structure and FunctionProteins Associate into Multimeric Structuresand Macromolecular AssembliesMultimeric proteins consist of two or more polypeptides orsubunits. A fourth level of structural organization, quaternarystructure, describes the number (stoichiometry) and relativepositions of the subunits in multimeric proteins. Hemagglutinin, for example, is a trimer of three identical subunits heldtogether by noncovalent bonds (Figure 3-7b).
Other multimeric proteins can be composed of any number of identical ordifferent subunits. The multimeric nature of many proteinsis critical to mechanisms for regulating their function. In addition, enzymes in the same pathway may be associated assubunits of a large multimeric protein within the cell, therebyincreasing the efficiency of pathway operation.The highest level of protein structure is the associationof proteins into macromolecular assemblies.
Typically, suchstructures are very large, exceeding 1 mDa in mass, approaching 30–300 nm in size, and containing tens to hundreds of polypeptide chains, as well as nucleic acids in someTABLE 3-1cases. Macromolecular assemblies with a structural functioninclude the capsid that encases the viral genome and bundlesof cytoskeletal filaments that support and give shape to theplasma membrane. Other macromolecular assemblies act asmolecular machines, carrying out the most complex cellularprocesses by integrating individual functions into one coordinated process.
For example, the transcriptional machinethat initiates the synthesis of messenger RNA (mRNA) consists of RNA polymerase, itself a multimeric protein, and atleast 50 additional components including general transcription factors, promoter-binding proteins, helicase, and otherprotein complexes (Figure 3-9). The transcription factorsand promoter-binding proteins correctly position a polymerase molecule at a promoter, the DNA site that determineswhere transcription of a specific gene begins. After helicaseunwinds the double-stranded DNA molecule, polymerase simultaneously translocates along the DNA template strandand synthesizes an mRNA strand.
The operational details ofthis complex machine and of others listed in Table 3-1 arediscussed elsewhere.Selected Molecular MachinesMachine*Main ComponentsCellular LocationFunctionReplisome (4)Helicase, primase, DNA polymeraseNucleusDNA replicationTranscription initiationcomplex (11)Promoter-binding protein, helicase,general transcription factors (TFs), RNApolymerase, large multisubunit mediatorcomplexNucleusRNA synthesisSpliceosome (12)Pre-mRNA, small nuclear RNAs(snRNAs), protein factorsNucleusmRNA splicingNuclear porecomplex (12)Nucleoporins (50–100)Nuclear membraneNuclear importand exportRibosome (4)Ribosomal proteins (50) and fourrRNA molecules (eukaryotes) organizedinto large and small subunits; associatedmRNA and protein factors (IFs, EFs)Cytoplasm/ER membraneProtein synthesisChaperonin (3)GroEL, GroES (bacteria)Cytoplasm,mitochondria,endoplasmicreticulumProtein foldingProteasome (3)Core proteins, regulatory (cap) proteinsCytoplasmProtein degradationPhotosystem (8)Light-harvesting complex (multipleproteins and pigments), reaction center(multisubunit protein with associatedpigments and electron carriers)Thylakoid membranein plant chloroplasts,plasma membrane ofphotosynthetic bacteriaPhotosynthesis(initial stage)MAP kinasecascades (14)Scaffold protein, multiple differentprotein kinasesCytoplasmSignal transductionSarcomere (19)Thick (myosin) filaments, thin (actin)filaments, Z lines, titin/nebulinCytoplasm ofmuscle cellsContraction*Numbers in parentheses indicate chapters in which various machines are discussed.3.1 • Hierarchical Structure of ProteinsMembers of Protein Families Have a CommonEvolutionary AncestorGeneral transcription factors+67+RNA polymeraseMediatorcomplexDNAPromoterTranscriptionpreinitiationcomplex▲ FIGURE 3-9 The mRNA transcription-initiation machinery.The core RNA polymerase, general transcription factors, amediator complex containing about 20 subunits, and otherprotein complexes not depicted here assemble at a promoter inDNA.
The polymerase carries out transcription of DNA; theassociated proteins are required for initial binding of polymeraseto a specific promoter, thereby initiating transcription.Studies on myoglobin and hemoglobin, the oxygen-carryingproteins in muscle and blood, respectively, provided early evidence that function derives from three-dimensional structure, which in turn is specified by amino acid sequence.X-ray crystallographic analysis showed that the threedimensional structures of myoglobin and the and subunits of hemoglobin are remarkably similar.
Subsequent sequencing of myoglobin and the hemoglobin subunitsrevealed that many identical or chemically similar residuesare found in identical positions throughout the primarystructures of both proteins.Similar comparisons between other proteins conclusivelyconfirmed the relation between the amino acid sequence,three-dimensional structure, and function of proteins. Thisprinciple is now commonly employed to predict, on thebasis of sequence comparisons with proteins of knownstructure and function, the structure and function of proteins that have not been isolated (Chapter 9). This use ofsequence comparisons has expanded substantially in recentyears as the genomes of more and more organisms havebeen sequenced.The molecular revolution in biology during the lastdecades of the twentieth century also created a new schemeααVertebrateHEMOGLOBINαβMYOGLOBINDicotMonocothemoglobin LEGHEMOGLOBIN hemoglobinAnnelidInsectNematodeββHemoglobinProtozoanAlgalFungalBacterialAncestraloxygen-bindingprotein▲ FIGURE 3-10 Evolution of the globin protein family.
(Left)A primitive monomeric oxygen-binding globin is thought to be theancestor of modern-day blood hemoglobins, muscle myoglobins,and plant leghemoglobins. Sequence comparisons have revealedthat evolution of the globin proteins parallels the evolution ofanimals and plants. Major junctions occurred with the divergenceof plant globins from animal globins and of myoglobin fromhemoglobin.
Later gene duplication gave rise to the and Leghemoglobinβ subunitof hemoglobinMyoglobinsubunits of hemoglobin. (Right) Hemoglobin is a tetramer of two and two subunits. The structural similarity of these subunitswith leghemoglobin and myoglobin, both of which aremonomers, is evident. A heme molecule (red) noncovalentlyassociated with each globin polypeptide is the actual oxygenbinding moiety in these proteins. [(Left) Adapted from R. C.Hardison, 1996, Proc. Natl.
Acad. Sci. USA 93:5675.]68CHAPTER 3 • Protein Structure and Functionof biological classification based on similarities and differences in the amino acid sequences of proteins. Proteins thathave a common ancestor are referred to as homologs. Themain evidence for homology among proteins, and hencetheir common ancestry, is similarity in their sequences orstructures. We can therefore describe homologous proteinsas belonging to a “family” and can trace their lineage fromcomparisons of their sequences. The folded three-dimensional structures of homologous proteins are similar even ifparts of their primary structure show little evidence ofhomology.The kinship among homologous proteins is most easilyvisualized by a tree diagram based on sequence analyses.
Forexample, the amino acid sequences of globins from bacteria,plants, and animals suggest that they evolved from an ancestral monomeric, oxygen-binding protein (Figure 3-10).With the passage of time, the gene for this ancestral proteinslowly changed, initially diverging into lineages leading toanimal and plant globins. Subsequent changes gave rise tomyoglobin, a monomeric oxygen-storing protein in muscle,and to the and subunits of the tetrameric hemoglobinmolecule (22) of the circulatory system.KEY CONCEPTS OF SECTION 3.1Hierarchical Structure of ProteinsA protein is a linear polymer of amino acids linkedtogether by peptide bonds. Various, mostly noncovalent,interactions between amino acids in the linear sequencestabilize a specific folded three-dimensional structure (conformation) for each protein.■The helix, strand and sheet, and turn are the mostprevalent elements of protein secondary structure, whichis stabilized by hydrogen bonds between atoms of the peptide backbone.■Certain combinations of secondary structures give riseto different motifs, which are found in a variety of proteins and are often associated with specific functions (seeFigure 3-6).■Protein tertiary structure results from hydrophobic interactions between nonpolar side groups and hydrogenbonds between polar side groups that stabilize folding ofthe secondary structure into a compact overall arrangement, or conformation.■■ Large proteins often contain distinct domains, independently folded regions of tertiary structure with characteristicstructural or functional properties or both (see Figure 3-7).The incorporation of domains as modules in differentproteins in the course of evolution has generated diversityin protein structure and function.■Quaternary structure encompasses the number and organization of subunits in multimeric proteins.■Cells contain large macromolecular assemblies in whichall the necessary participants in complex cellular processes(e.g., DNA, RNA, and protein synthesis; photosynthesis;signal transduction) are integrated to form molecular machines (see Table 3-1).■■ The sequence of a protein determines its three-dimensionalstructure, which determines its function.
In short, functionderives from structure; structure derives from sequence.Homologous proteins, which have similar sequences,structures, and functions, evolved from a common ancestor.■3.2 Folding, Modification,and Degradation of ProteinsA polypeptide chain is synthesized by a complex process calledtranslation in which the assembly of amino acids in a particular sequence is dictated by messenger RNA (mRNA). The intricacies of translation are considered in Chapter 4. Here, wedescribe how the cell promotes the proper folding of a nascent polypeptide chain and, in many cases, modifies residuesor cleaves the polypeptide backbone to generate the final protein.
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