Copper binding to the neurotoxic peptide PrP106-126:: Thermodynamic and structural studies

被引:65
作者
Belosi, B
Gaggelli, E
Guerrini, R
Kozlowski, H
Luczkowski, M
Mancini, FM
Remelli, M
Valensin, D
Valensin, G
机构
[1] Univ Wroclaw, Fac Chem, PL-50383 Wroclaw, Poland
[2] Univ Ferrara, Dipartimento Chim, I-44100 Ferrara, Italy
[3] Univ Siena, Dipartimento Chim, I-53100 Siena, Italy
[4] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy
关键词
bioinorganic chemistry; complexes; copper; peptides; prion proteins;
D O I
10.1002/cbic.200300786
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The human prion protein fragment PrP106-126 is a highly fibrillogenic peptide, resistant to proteinases and toxic to neurons; it derives from the normal prion protein (PrPC), with which it can interact, thus inhibiting its superoxide dismutase-like activity. The same properties are also shown by the abnormal isoform of the prion protein (PrPSc), and this similarity makes PrP106-126 an interesting model for the neurotoxic action of PrPSc. A role for copper in PrP106-126 aggregation and toxicity has recently been evidenced, and the interaction of terminal Lys, His and Met residues with the copper ion at neutral pH has been suggested. In order to shed more light on the the complex-formation equilibria of PrP106-126 with the copper ion, a thorough investigation has been carried out by means of several experimental techniques: potentiometry, solution calorimetry, VIS spectrophotometry, circular dichroism, EPR and NMR spectroscopy. A shorter and more soluble fragment-PrP106-113, which lacks the hydrophobic C-terminal domain of PrP106-126 but contains all the potential donor groups-has also been considered for the sake of comparison. The involvement of terminal amino, imidazolic and amido nitrogens in complex formation has been confirmed, while no evidence was found for the interaction of side chains of Met and Lys residues with the copper ion. Solution structures for the main complexes are suggested.
引用
收藏
页码:349 / 359
页数:11
相关论文
共 56 条
[1]   Hyperquad simulation and speciation (HySS): a utility program for the investigation of equilibria involving soluble and partially soluble species [J].
Alderighi, L ;
Gans, P ;
Ienco, A ;
Peters, D ;
Sabatini, A ;
Vacca, A .
COORDINATION CHEMISTRY REVIEWS, 1999, 184 :311-318
[2]  
Atherton E., 1989, SOLID PHASE PEPTIDE
[3]   Dramatic aggregation of Alzheimer Aβ by Cu(II) is induced by conditions representing physiological acidosis [J].
Atwood, CS ;
Moir, RD ;
Huang, XD ;
Scarpa, RC ;
Bacarra, NME ;
Romano, DM ;
Hartshorn, MK ;
Tanzi, RE ;
Bush, AI .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (21) :12817-12826
[4]   PRIMARY STRUCTURE EFFECTS ON PEPTIDE GROUP HYDROGEN-EXCHANGE [J].
BAI, YW ;
MILNE, JS ;
MAYNE, L ;
ENGLANDER, SW .
PROTEINS-STRUCTURE FUNCTION AND GENETICS, 1993, 17 (01) :75-86
[5]  
BELOSI B, UNPUB
[6]   NONCOVALENT INTERACTIONS IN THERMODYNAMIC STEREOSELECTIVITY OF MIXED-LIGAND COPPER(II)-D-HISTIDINE OR L-HISTIDINE COMPLEXES WITH L-AMINO-ACIDS - A POSSIBLE MODEL OF METAL ION-ASSISTED MOLECULAR RECOGNITION [J].
BORGHESANI, G ;
PULIDORI, F ;
REMELLI, M ;
PURRELLO, R ;
RIZZARELLI, E .
JOURNAL OF THE CHEMICAL SOCIETY-DALTON TRANSACTIONS, 1990, (07) :2095-2100
[7]   Spongiform encephalopathies - B lymphocytes and neuroinvasion [J].
Brown, P .
NATURE, 1997, 390 (6661) :662-663
[8]   Role of microglia and host prion protein in neurotoxicity of a prion protein fragment [J].
Brown, DR ;
Schmidt, B ;
Kretzschmar, HA .
NATURE, 1996, 380 (6572) :345-347
[9]   Copper-dependent functions for the prion protein [J].
Brown, DR ;
Sassoon, J .
MOLECULAR BIOTECHNOLOGY, 2002, 22 (02) :165-178
[10]   MOUSE CORTICAL-CELLS LACKING CELLULAR PRP SURVIVE IN CULTURE WITH A NEUROTOXIC PRP FRAGMENT [J].
BROWN, DR ;
HERMS, J ;
KRETZSCHMAR, HA .
NEUROREPORT, 1994, 5 (16) :2057-2060