Structural Models for Cu(II) Bound to the Fragment 92-96 of the Human Prion Protein

被引:20
作者
Grande-Aztatzi, Rafael [1 ]
Rivillas-Acevedo, Lina [1 ]
Quintanar, Liliana [1 ]
Vela, Alberto [1 ]
机构
[1] CINVESTAV, Dept Quim, Mexico City 07360, DF, Mexico
关键词
N-TERMINAL DOMAIN; BINDING-SITES; FULL-LENGTH; OCTAREPEAT DOMAIN; COPPER-BINDING; COORDINATION MODES; BASIS-SETS; G-TENSORS; COMPLEXES; METAL;
D O I
10.1021/jp310000h
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
The prion protein (PrPC) binds Cu(II) in its N-terminal region, and it is associated to a group of neurodegenerative diseases termed transmissible spongiform encephalopaties (TSEs). The isoform PrPSc, derived from the normal PrPC, is the pathogenic agent of TSEs. Using spectroscopic techniques (UV-vis absorption, circular dichroism, and electron paramagnetic resonance) and electronic structure calculations, we obtained a structural description for the different pH-dependent binding modes of Cu(II) to the PrP(92-96) fragment. We have also evaluated the possibility of water molecule ligation to the His96-bound copper ion. Geometry-optimized structural models that reproduce the spectroscopic features of these complexes are presented. Two Cu(II) binding modes are relevant at physiological pH: 4N and 3NO equatorial coordination modes; these are best described by models with no participation of water molecules in the coordination sphere of the metal ion. In contrast, the 2N2O and N3O coordination modes that are formed at lower pH involve the coordination of an axial water molecule. This study underscores the importance of including explicit water molecules when modeling copper binding sites in PrPC.
引用
收藏
页码:789 / 799
页数:11
相关论文
共 73 条
[1]   Toward reliable density functional methods without adjustable parameters: The PBE0 model [J].
Adamo, C ;
Barone, V .
JOURNAL OF CHEMICAL PHYSICS, 1999, 110 (13) :6158-6170
[2]  
[Anonymous], 2001, DENSITY FUNCTIONAL T
[3]   Identification of the Cu2+ binding sites in the N-terminal domain of the prion protein by EPR and CD spectroscopy [J].
Aronoff-Spencer, E ;
Burns, CS ;
Avdievich, NI ;
Gerfen, GJ ;
Peisach, J ;
Antholine, WE ;
Ball, HL ;
Cohen, FE ;
Prusiner, SB ;
Millhauser, GL .
BIOCHEMISTRY, 2000, 39 (45) :13760-13771
[4]   The affinity of HGGG, GHGG, GGHG, and GGGH peptides for copper(II) and the structures of their complexes - An ab initio study1 [J].
Barry, Stephen D. ;
Rickard, Gail A. ;
Pushie, M. Jake ;
Rauk, Arvi .
CANADIAN JOURNAL OF CHEMISTRY, 2009, 87 (07) :942-953
[5]   ELECTRONIC-SPECTRA OF COPPER(II)-IMIDAZOLE AND COPPER(II)-PYRAZOLE CHROMOPHORES [J].
BERNARDUCCI, E ;
SCHWINDINGER, WF ;
HUGHEY, JL ;
KROGHJESPERSEN, K ;
SCHUGAR, HJ .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1981, 103 (07) :1686-1691
[6]   Structural and dynamic characterization of copper(11) binding of the human prion protein outside the octarepeat region [J].
Berti, Francesco ;
Gaggelli, Elena ;
Guerrini, Remo ;
Janicka, Anna ;
Kozlowski, Henryk ;
Legowska, Anna ;
Miecznikowska, Hanna ;
Migliorini, Caterina ;
Pogni, Rebecca ;
Remelli, Maurizio ;
Rolka, Krzysztof ;
Valensin, Daniela ;
Valensin, Gianni .
CHEMISTRY-A EUROPEAN JOURNAL, 2007, 13 (07) :1991-2001
[7]   Prion protein protects human neurons against Bax-mediated apoptosis [J].
Bounhar, Y ;
Zhang, Y ;
Goodyer, CG ;
LeBlanc, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (42) :39145-39149
[8]   TYPE 2 COPPER(II) AS A COMPONENT OF DIOXYGEN REDUCING SITE IN LACCASE - EVIDENCE FROM EPR EXPERIMENTS WITH O-17 [J].
BRANDEN, R ;
DEINUM, J .
FEBS LETTERS, 1977, 73 (02) :144-146
[9]   Spongiform encephalopathies - B lymphocytes and neuroinvasion [J].
Brown, P .
NATURE, 1997, 390 (6661) :662-663
[10]   Normal prion protein has an activity like that of superoxide dismutase [J].
Brown, DR ;
Wong, BS ;
Hafiz, F ;
Clive, C ;
Haswell, SJ ;
Jones, IM .
BIOCHEMICAL JOURNAL, 1999, 344 :1-5