Harpers

PROTEINS: HIGHER ORDERS OF STRUCTURE / 37shaped hsp60 chaperone provides a sheltered environmentin which a polypeptide can fold until all hydrophobicregions are buried in its interior, eliminatingaggregation. Chaperone proteins can also “rescue” proteinsthat have become thermodynamically trapped in amisfolded dead end by unfolding hydrophobic regionsand providing a second chance to fold productively.Protein Disulfide IsomeraseDisulfide bonds between and within polypeptides stabilizetertiary and quaternary structure. However, disulfidebond formation is nonspecific. Under oxidizingconditions, a given cysteine can form a disulfide bondwith the ⎯SH of any accessible cysteinyl residue. Bycatalyzing disulfide exchange, the rupture of an S⎯Sbond and its reformation with a different partner cysteine,protein disulfide isomerase facilitates the formationof disulfide bonds that stabilize their native conformation.Proline-cis,trans-IsomeraseAll X-Pro peptide bonds—where X represents anyresidue—are synthesized in the trans configuration.However, of the X-Pro bonds of mature proteins, approximately6% are cis. The cis configuration is particularlycommon in β-turns. Isomerization from trans tocis is catalyzed by the enzyme proline-cis,trans-isomerase(Figure 5–9).SEVERAL NEUROLOGIC DISEASESRESULT FROM ALTERED PROTEINCONFORMATIONPrionsThe transmissible spongiform encephalopathies, orprion diseases, are fatal neurodegenerative diseasescharacterized by spongiform changes, astrocytic gliomas,and neuronal loss resulting from the depositionof insoluble protein aggregates in neural cells. They includeCreutzfeldt-Jakob disease in humans, scrapie inOO OHH α 1 ′NNα 1 Nα 1 NR 1 α 1 ′R 1OFigure 5–9. Isomerization of the N-α 1 prolyl peptidebond from a cis to a trans configuration relative to thebackbone of the polypeptide.sheep, and bovine spongiform encephalopathy (madcow disease) in cattle. Prion diseases may manifestthemselves as infectious, genetic, or sporadic disorders.Because no viral or bacterial gene encoding the pathologicprion protein could be identified, the source andmechanism of transmission of prion disease long remainedelusive. Today it is believed that prion diseasesare protein conformation diseases transmitted by alteringthe conformation, and hence the physical properties,of proteins endogenous to the host. Human prionrelatedprotein, PrP, a glycoprotein encoded on theshort arm of chromosome 20, normally is monomericand rich in α helix. Pathologic prion proteins serve asthe templates for the conformational transformation ofnormal PrP, known as PrPc, into PrPsc. PrPsc is rich inβ sheet with many hydrophobic aminoacyl side chainsexposed to solvent. PrPsc molecules therefore associatestrongly with one other, forming insoluble protease-resistantaggregates. Since one pathologic prion or prionrelatedprotein can serve as template for the conformationaltransformation of many times its number of PrPcmolecules, prion diseases can be transmitted by the proteinalone without involvement of DNA or RNA.Alzheimer’s DiseaseRefolding or misfolding of another protein endogenousto human brain tissue, β-amyloid, is also a prominentfeature of Alzheimer’s disease. While the root cause ofAlzheimer’s disease remains elusive, the characteristicsenile plaques and neurofibrillary bundles contain aggregatesof the protein β-amyloid, a 4.3-kDa polypeptideproduced by proteolytic cleavage of a larger proteinknown as amyloid precursor protein. In Alzheimer’sdisease patients, levels of β-amyloid become elevated,and this protein undergoes a conformational transformationfrom a soluble α helix–rich state to a state richin β sheet and prone to self-aggregation. ApolipoproteinE has been implicated as a potential mediator ofthis conformational transformation.COLLAGEN ILLUSTRATES THE ROLE OFPOSTTRANSLATIONAL PROCESSING INPROTEIN MATURATIONProtein Maturation Often Involves Making& Breaking Covalent BondsThe maturation of proteins into their final structuralstate often involves the cleavage or formation (or both)of covalent bonds, a process termed posttranslationalmodification. Many polypeptides are initially synthesizedas larger precursors, called proproteins. The“extra” polypeptide segments in these proproteinsoften serve as leader sequences that target a polypeptide