Soft Report - Dipartimento di Fisica - Sapienza

Scientific Report – Self Assembly, Clustering, Structural arrestRole of metal ions in protein aggregation processesAmyloidosis is a family of pathologies caused by thetransition of endogenous proteins and peptides fromthe physiological globular configuration to apathological fibrillar state. The term amyloidosisdescribes a heterogeneous group of diseases (morethan 20), which are characterized by extra-cellulardeposition of fibrillar material. Among them, theAlzheimer’s disease (AD) is a progressive anddevastating neurodegenerative pathology affectingan important fraction of the aged population in thedeveloped world. AD is characterized by memorydisorders, degradation of the personality and otherbehavioural abnormalities correlated to the loss ofneurons from cortex and hippocampus. These eventsare accompanied by peculiar morphologicalmanifestations like formation of senile plaques in thebrain, amyloidosis of brain vessels and intraneuronaldeposits of amyloid fibrils. The majorcomponent of the AD amyloid plaques are the β-amyloid peptides (Aβ). It has been observed thatplaques contain large amounts of transition metalslike Cu, Fe and Zn (the last one being the mostabundant). Their role is not yet fully understood, butit has been conjectured to be crucial in thepathological effects of AD. X-ray absorptionspectroscopy (XAS) can be profitably used forstructural studies on biological material [1-3], as thetechnique can be employed for samples in any stateof aggregation, in particular for proteins in solution,thus allowing investigations in physiologicalconditions. Owing to its chemical selectivity andsensitivity to the local atomic arrangement aroundthe absorber, one can get a clear-cut identification ofthe amino acid residues primarily bound to themetal. XAS has been used to investigate the localstructure around the ion in samples of Aβ-peptidescomplexed with Cu 2+ or Zn 2+ . Our data showdifferent metal binding site structures in β-amyloidpeptides according to whether they are complexedwith Cu 2+ or Zn 2+ ions. While the geometry aroundcopper is stably consistent with an intra-peptidebinding with three metal-coordinated Histidineresidues, the zinc coordination mode depends onspecific solution conditions. In particular, differentsample preparations are seen to lead to differentgeometries around the absorber that are compatiblewith either an intra- or an inter-peptide coordinationmode (fig. 1). This result reinforces the hypothesisthat assigns different physiological roles to the twometals, with Zn favoring peptide aggregation and, asa consequence, plaque formation. The human priona) b) c)Fig. 1: Schematic illustration of the structures of(Cu–Aβ) 1 (panel a), (Zn–Aβ) 1 (panel b) and (Zn–Aβ) 2(panel c), as they emerge from the fit to the data.Only metal–Histidine bonds are explicitly shown. TheAβ-peptide backbone is drawn as a shoe string (fromRef. [3])protein binds Cu 2+ ions in the octarepeat domain ofthe N-terminal tail up to full occupancy at pH=7.4.Recent experiments show that the HGGG octarepeatsub-domain is responsible for holding the metalbound in a square planar configuration. On thenumerical side [4-6], we have approached a similarproblem which has to do with cellular prion protein(PrP c ). PrP c is a cell surface glycoprotein that isconsidered a key molecule for the understanding ofthe development of a group of neuro-degenerativediseases, generically referred to as “prion diseases”.Prion diseases are characterized by theconformational transition of the native,predominantly α-helical, PrP c , into a pathogenic,mostlyβ-sheet,conformer called scrapie,PrP Sc .The human prion proteinbinds Cu 2+ ions in theoctarepeat domain of theN-terminal tail up to fulloccupancy at pH=7.4.Recent experiments showthat the HGGG octarepeatsub-domain is responsible for holding the metalbound in a square planar configuration. By using firstprinciple ab initio molecular dynamics simulations ofthe Car-Parrinello type, we have investigated thecoordination of Cu to the binding sites of the prionprotein octarepeat region [7]. Simulations arecarried out for the complexes Cu(HGGGW)(wat),Cu(HGGG) and [Cu(HGGG)] 2. While the presence ofa Trp residue and a water molecule does not affectthe nature of the Cu coordination, high stability ofthe bond between Cu and the amide nitrogen ofdeprotonated Gly’s is confirmed in all cases. For themore interesting [Cu(HGGG)] 2 complex adynamically entangled arrangement of the twodomains with exchange of amide nitrogen bondsbetween the two Cu centers emerges (fig. 2), whichis consistent with the short Cu-Cu distance observedin experiments at full Cu occupancy.Fig. 2: Structure of the [Cu(HG − G − G)] 2 systemobtained in the (spin-restricted simulation) atT=300 K and at t=0.86 ps (from Ref. [7])References[1] S.Morante, et al., J. Biol. Chem. 279, 11753(2004).[2] M.Benfatto, et al., Biophys. Chem. 110, 191(2004).[3] F.Stellato, et al., Eur. Biophys. J. 35(4), 340(2006).[4] G. La Penna, et al., Int. J. Mod. Phys. C 15, 205(2004).[5] G.La Penna, et al., J. Chem. Phys. 121, 10725(2004).[6] S.Morante, et al., J. Chem. Phys. 125. 034101(2006)AuthorsF. Guerrieri (a, c), V. Minicozzi (a), S. Morante (a, b, c),G. C. Rossi (a, c), F. Stellato (a, c)(a) Dip. di Fisica, Univ. di Roma Tor Vergata, Roma II(b) CRS SOFT-INFM-CNR, Roma, Italy(c) INFN, Sez. di Roma Tor VergataSOFT Scientific Report 2004-0690