Lodish H. - Molecular Cell Biology (5ed, Freeman, 2003) (794361), страница 31
Текст из файла (страница 31)
Both contain sequences recognized by the ubiquitinating enzyme complex.The cyclins, for example, are cytosolic proteins whoseamounts are tightly controlled throughout the cell cycle.These proteins contain the internal sequence Arg-X-X-LeuGly-X-Ile-Gly-Asp/Asn (X can be any amino acid), which isrecognized by specific ubiquitinating enzyme complexes. Ata specific time in the cell cycle, each cyclin is phosphorylatedby a cyclin kinase. This phosphorylation is thought to causea conformational change that exposes the recognition sequence to the ubiquitinating enzymes, leading to degradationof the tagged cyclin (Chapter 21).
Similarly, the misfolding ofproteins in the endoplasmic reticulum exposes hydrophobicsequences normally buried within the folded protein. Suchproteins are transported to the cytosol, where ubiquitinating enzymes recognize the exposed hydrophobic sequences.The immune system also makes use of the ubiquitinmediated pathway in the response to altered self-cells, particularly virus-infected cells.
Viral proteins within the cytosolof infected cells are ubiquitinated and then degraded in proteasomes specially designed for this role. The resulting antigenic peptides are transported to the endoplasmic reticulum,where they bind to class I major histocompatibility complex(MHC) molecules within the ER membrane. Subsequently,the peptide-MHC complexes move to the cell membranewhere the antigenic peptides can be recognized by cytotoxicT lymphocytes, which mediate the destruction of the infectedcells.Alternatively Folded Proteins Are Implicated inSlowly Developing DiseasesAs noted earlier, each protein species normally foldsinto a single, energetically favorable conformationthat is specified by its amino acid sequence. Recentevidence suggests, however, that a protein may fold into an alternative three-dimensional structure as the result of mutations, inappropriate post-translational modification, or otheras-yet-unidentified reasons.
Such “misfolding” not only leadsto a loss of the normal function of the protein but also marksit for proteolytic degradation. The subsequent accumulationof proteolytic fragments contributes to certain degenerativediseases characterized by the presence of insoluble proteinplaques in various organs, including the liver and brain. ❚Some neurodegenerative diseases, including Alzheimer’sdisease and Parkinson’s disease in humans and transmissiblespongiform encephalopathy (“mad cow” disease) in cows(b)(a)Digestive Proteases Degrade Dietary ProteinsThe major extracellular pathway for protein degradation is thesystem of digestive proteases that breaks down ingested proteins into peptides and amino acids in the intestinal tract.Three classes of proteases function in digestion.
Endoproteasesattack selected peptide bonds within a polypeptide chain. Theprincipal endoproteases are pepsin, which preferentiallycleaves the backbone adjacent to phenylalanine and leucineresidues, and trypsin and chymotrypsin, which cleave thebackbone adjacent to basic and aromatic residues. Exopeptidases sequentially remove residues from the N-terminus(aminopeptidases) or C-terminus (carboxypeptidases) of aprotein. Peptidases split oligopeptides containing as many asabout 20 amino acids into di- and tripeptides and individualamino acids.
These small molecules are then transportedacross the intestinal lining into the bloodstream.To protect a cell from degrading itself, endoproteases andcarboxypeptidases are synthesized and secreted as inactiveforms (zymogens): pepsin by chief cells in the lining of thestomach; the others by pancreatic cells. Proteolytic cleavageof the zymogens within the gastic or intestinal lumen yieldsthe active enzymes. Intestinal epithelial cells produceaminopeptidases and the di- and tripeptidases.20 m100 nm▲ EXPERIMENTAL FIGURE 3-14 Alzheimer’s disease ischaracterized by the formation of insoluble plaquescomposed of amyloid protein. (a) At low resolution, an amyloidplaque in the brain of an Alzheimer’s patient appears as a tangleof filaments.
(b) The regular structure of filaments from plaquesis revealed in the atomic force microscope. Proteolysis of thenaturally occurring amyloid precursor protein yields a shortfragment, called -amyloid protein, that for unknown reasonschanges from an -helical to a -sheet conformation. Thisalternative structure aggregates into the highly stable filaments(amyloid) found in plaques. Similar pathologic changes in otherproteins cause other degenerative diseases. [Courtesy of K. Kosik.]3.3 • Enzymes and the Chemical Work of Cellsand sheep, are marked by the formation of tangled filamentous plaques in a deteriorating brain (Figure 3-14).
The amyloid filaments composing these structures derive fromabundant natural proteins such as amyloid precursor protein, which is embedded in the plasma membrane, Tau, amicrotubule-binding protein, and prion protein, an “infectious” protein whose inheritance follows Mendelian genetics.Influenced by unknown causes, these helix–containing proteins or their proteolytic fragments fold into alternative sheet–containing structures that polymerize into very stablefilaments.
Whether the extracellular deposits of these filaments or the soluble alternatively folded proteins are toxic tothe cell is unclear.73degree of specificity. For instance, an enzyme must first bindspecifically to its target molecule, which may be a small molecule (e.g., glucose) or a macromolecule, before it can executeits specific task. Likewise, the many different types of hormone receptors on the surface of cells display a high degree ofsensitivity and discrimination for their ligands. And, as wewill examine in Chapter 11, the binding of certain regulatoryproteins to specific sequences in DNA is a major mechanismfor controlling genes. Ligand binding often causes a change inthe shape of a protein.
Ligand-driven conformational changesare integral to the mechanism of action of many proteins andare important in regulating protein activity. After considering the general properties of protein–ligand binding, we takea closer look at how enzymes are designed to function as thecell’s chemists.KEY CONCEPTS OF SECTION 3.2Folding, Modification, and Degradation of ProteinsThe amino acid sequence of a protein dictates its folding into a specific three-dimensional conformation, the native state.■Protein folding in vivo occurs with assistance from molecular chaperones (Hsp70 proteins), which bind to nascent polypeptides emerging from ribosomes and preventtheir misfolding (see Figure 3-11).
Chaperonins, large complexes of Hsp60-like proteins, shelter some partly foldedor misfolded proteins in a barrel-like cavity, providing additional time for proper folding.■Subsequent to their synthesis, most proteins are modified by the addition of various chemical groups to aminoacid residues. These modifications, which alter proteinstructure and function, include acetylation, hydroxylation,glycosylation, and phosphorylation.■The life span of intracellular proteins is largely determined by their susceptibility to proteolytic degradation byvarious pathways.■Viral proteins produced within infected cells, normal cytosolic proteins, and misfolded proteins are marked for destruction by the covalent addition of a polyubiquitin chainand then degraded within proteasomes, large cylindricalcomplexes with multiple proteases in their interiors (seeFigure 3-13).■Some neurodegenerative diseases are caused by aggregates of proteins that are stably folded in an alternativeconformation.■3.3 Enzymes and the Chemical Workof CellsProteins are designed to bind every conceivable molecule—from simple ions and small metabolites (sugars, fatty acids) tolarge complex molecules such as other proteins and nucleicacids.
Indeed, the function of nearly all proteins depends ontheir ability to bind other molecules, or ligands, with a highSpecificity and Affinity of Protein–Ligand BindingDepend on Molecular ComplementarityTwo properties of a protein characterize its interaction withligands. Specificity refers to the ability of a protein to bindone molecule in preference to other molecules.
Affinityrefers to the strength of binding. The Kd for a protein–ligand complex, which is the inverse of the equilibrium constant Keq for the binding reaction, is the most commonquantitative measure of affinity (Chapter 2). The strongerthe interaction between a protein and ligand, the lower thevalue of Kd. Both the specificity and the affinity of a proteinfor a ligand depend on the structure of the ligand-bindingsite, which is designed to fit its partner like a mold.
Forhigh-affinity and highly specific interactions to take place,the shape and chemical surface of the binding site must becomplementary to the ligand molecule, a property termedmolecular complementarity.The ability of proteins to distinguish different moleculesis perhaps most highly developed in the blood proteins calledantibodies, which animals produce in response to antigens,such as infectious agents (e.g., a bacterium or a virus), andcertain foreign substances (e.g., proteins or polysaccharidesin pollens). The presence of an antigen causes an organism tomake a large quantity of different antibody proteins, eachof which may bind to a slightly different region, or epitope,of the antigen.
![](https://s.studizba.com/z.php?f=/templates/si/i/noavatar.png&w=100&h=100&t=1"){kind=avatar}
