B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 50
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This is the mechanism that determines the length of the TMV particle, where the RNA chain provides the core.Similarly, a core protein interactingMBoC6withm3.31/3.27actin is thought to determine the lengthof the thin filaments in muscle.(A)50 nm(B)Figure 3–29 The structure of tobacco mosaic virus (TMV). (A) An electron micrograph of the viral particle, which consists ofa single long RNA molecule enclosed in a cylindrical protein coat composed of identical protein subunits.
(B) A model showingpart of the structure of TMV. A single-stranded RNA molecule of 6395 nucleotides is packaged in a helical coat constructedfrom 2130 copies of a coat protein 158 amino acids long. Fully infective viral particles can self-assemble in a test tube frompurified RNA and protein molecules. (A, courtesy of Robley Williams; B, courtesy of Richard J. Feldmann.)MBoC6 m3.32/3.28130Chapter 3: ProteinsFigure 3–30 Proteolytic cleavage in insulin assembly.
The polypeptidehormone insulin cannot spontaneously re-form efficiently if its disulfide bondsare disrupted. It is synthesized as a larger protein (proinsulin) that is cleavedby a proteolytic enzyme after the protein chain has folded into a specificshape. Excision of part of the proinsulin polypeptide chain removes some ofthe information needed for the protein to fold spontaneously into its normalconformation. Once insulin has been denatured and its two polypeptidechains have separated, its ability to reassemble is lost.proinsulinSHSHSSSSSSconnecting peptideremoved, leavingcomplete two-chaininsulin moleculeSinsulinSSSSSreduction irreversiblyseparates the two chainsSHSHSH+SHSHAmyloid Fibrils Can Form from Many ProteinsA special class of protein structures, utilized for some normal cell functions, canalso contribute to human diseases when not controlled.
These are self-propagating, stable β-sheet aggregates called amyloid fibrils. These fibrils are built from aseries of identical polypeptide chains that become layered one over the other tocreate a continuous stack of β sheets, with the β strands oriented perpendicularto the fibril axis to form a cross-beta filament (Figure 3–31). Typically, hundreds ofmonomers will aggregate to form an unbranched fibrous structure that is severalmicrometers long and 5 to 15 nm in width. A surprisingly large fraction of proteins have the potential to form such structures, because the short segment of thepolypeptide chain that forms the spine of the fibril can have a variety of differentsequences and follow one of several different paths (Figure 3–32).
However, veryfew proteins will actually form this structure inside cells.In normal humans, the quality control mechanisms governing proteins gradually decline with age, occasionally permitting normal proteins to form pathological aggregates. The protein aggregates may be released from dead cells andaccumulate as amyloid in the extracellular matrix. In extreme cases, the accumulation of such amyloid fibrils in the cell interior can kill the cells and damage tissues. Because the brain is composed of a highly organized collection of nerve cellsthat cannot regenerate, the brain is especially vulnerable to this sort of cumulative damage.
Thus, although amyloid fibrils may form in different tissues, and areknown to cause pathologies in several sites in the body, the most severe amyloidpathologies are neurodegenerative diseases. For example, the abnormal formation of highly stable amyloid fibrils is thought to play a central causative role inboth Alzheimer’s and Parkinson’s diseases.Prion diseases are a special type of these pathologies. They have attainedspecial notoriety because, unlike Parkinson’s or Alzheimer’s, prion diseases canspread from one organism to another, providing that the second organism eats aSHSHSHspecific folding stabilizedby disulfide bondsAssembly Factors Often Aid the Formation of Complex BiologicalStructuresNot all cellular structures held together by noncovalent bonds self-assemble.
A cilium, or a myofibril of a muscle cell, for example, cannot form spontaneously froma solution of its component macromolecules. In these cases, part of the assemblyinformation is provided by special enzymes and other proteins that perform thefunction of templates, serving as assembly factors that guide construction but takeno part in the final assembled structure.Even relatively simple structures may lack some of the ingredients necessaryfor their own assembly. In the formation of certain bacterial viruses, for example,the head, which is composed of many copies of a single protein subunit, is assembled on a temporary scaffold composed of a second protein that is produced bythe virus.
Because the second protein is absent from the final viral particle, thehead structure cannot spontaneously reassemble once it has been taken apart.Other examples are known in which proteolytic cleavage is an essential and irreversible step in the normal assembly process. This is even the case for some smallprotein assemblies, including the structural protein collagen and the hormoneinsulin (Figure 3–30).
From these relatively simple examples, it seems certain thatthe assembly of a structure as complex as a cilium will involve a temporal andspatial ordering that is imparted by numerous other components.SHMBoC6 m3.35/3.29SHTHE SHAPE AND STRUCTURE OF PROTEINS131Figure 3–31 Detailed structure of the core of an amyloid fibril. Illustrated hereis the cross-beta spine of the amyloid fibril that is formed by a peptide of sevenamino acids from the protein Sup35, an extensively studied yeast prion.
Consistingof the sequence glycine-asparagine-asparagine-glutamine-glutamine-asparaginetyrosine (GNNQQNY), its structure was determined by X-ray crystallography.Although the cross-beta spines of other amyloids are similar, being composed oftwo long β sheets held together by a “steric zipper,” different detailed structuresare observed depending on the short peptide sequence involved. (A) One halfof the spine is illustrated. Here, a standard parallel β-sheet structure (seep. 116) is held together by a set of hydrogen bonds between two side chains plushydrogen bonds between two backbone atoms, as illustrated (oxygen atoms redand nitrogen atoms blue). Note that in this example, the adjacent peptides areexactly in register. Although only five layers are shown (each layer depicted as anarrow), the actual structure would extend for many tens of thousands of layersin the plane of the paper.
(B) The complete cross-beta spine. A second, identicalβ-sheet is paired with the first one to form a two-sheet motif that runs the entirelength of the fibril. (C) View of the complete spine in (B) from the top. The closelyinterdigitated side chains form a tight, water-free junction known as a steric zipper.(Courtesy of David Eisenberg and Michael Sawaya, UCLA; based on R. Nelson etal., Nature 435:773–778, 2005.
With permission from Macmillan Publishers Ltd.)tissue containing the protein aggregate. A set of closely related diseases—scrapie in sheep, Creutzfeldt–Jakob disease (CJD) in humans, Kuru in humans, andbovine spongiform encephalopathy (BSE) in cattle—are caused by a misfolded,aggregated form of a particular protein called PrP (for prion protein). PrP is normally located on the outer surface of the plasma membrane, most prominently inneurons, and it has the unfortunate property of forming amyloid fibrils that are“infectious” because they convert normally folded molecules of PrP to the samepathological form (Figure 3–33).
This property creates a positive feedback loopthat propagates the abnormal form of PrP, called PrP*, and allows the pathologicalconformation to spread rapidly from cell to cell in the brain, eventually causingdeath. It can be dangerous to eat the tissues of animals that contain PrP*, as witnessed by the spread of BSE (commonly referred to as “mad cow disease”) fromcattle to humans. Fortunately, in the absence of PrP*, PrP is extraordinarily difficult to convert to its abnormal form.A closely related “protein-only inheritance” has been observed in yeast cells.The ability to study infectious proteins in yeast has clarified another remarkablefeature of prions.
These protein molecules can form several distinctively differenttypes of amyloid fibrils from the same polypeptide chain. Moreover, each type ofaggregate can be infectious, forcing normal protein molecules to adopt the sametype of abnormal structure. Thus, several different “strains” of infectious particlescan arise from the same polypeptide chain.side chain backboneH-bond(A) H-bond(B)(C)cross-beta spinecross-beta spine(A)MBoC6 n3.317/3.30.5relatively undefined peripheral domains(B)2 nm(C)100 nmFigure 3–32 The structure of an amyloidfibril. (A) Schematic diagram of thestructure of a amyloid fibril that is formedby the aggregation of a protein.
Onlythe cross-beta spine of an amyloid fibrilresembles the structure shown in Figure3–31. (B) A cut-away view of a structureproposed for the amyloid fibril that canbe formed in a test tube by the enzymeribonuclease A, illustrating how the coreof the fibril—formed by a short segment—relates to the rest of the structure.(C) Electron micrograph of amyloid fibrils.(A, from L. Esposito, C. Pedone andL. Vitagliano, Proc. Natl Acad. Sci.
USA103:11533–11538, 2006; B, from S.Sambashivan et al., Nature 437:266–269,2005; C, courtesy of David Eisenberg.)132Chapter 3: ProteinsFigure 3–33 The special protein aggregates that cause prion diseases.(A) Schematic illustration of the type of conformational change in the PrPprotein (prion protein) that produces material for an amyloid fibril. (B) The selfinfectious nature of the protein aggregation that is central to prion diseases.PrP is highly unusual because the misfolded version of the protein, calledPrP*, induces the normal PrP protein it contacts to change its conformation,as shown.(A) prion protein can adopt an abnormal,misfolded formvery rareconformationalchangenormal PrpproteinAmyloid Structures Can Perform Useful Functions in CellsAmyloid fibrils were initially studied because they cause disease.
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