| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Molecular Biophysics Group, CCLRC Daresbury Laboratory, Warrington, Cheshire, WA4 4AD, United Kingdom2 Department of Biochemistry and the X-ray Crystallography Core Laboratory, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA3 Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, USA4 Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA
(RECEIVED November 24, 2004; FINAL REVISION January 26, 2005; ACCEPTED January 26, 2005)
The His46Arg (H46R) mutant of human copper-zinc superoxide dismutase (SOD1) is associated with an unusual, slowly progressing form of familial amyotrophic lateral sclerosis (FALS). Here we describe in detail the crystal structures of pathogenic H46R SOD1 in the Zn-loaded (Zn-H46R) and metal-free (apo-H46R) forms. The Zn-H46R structure demonstrates a novel zinc coordination that involves only three of the usual four liganding residues, His 63, His 80, and Asp 83 together with a water molecule. In addition, the Asp 124 "secondary bridge" between the copper- and zinc-binding sites is disrupted, and the "electrostatic loop" and "zinc loop" elements are largely disordered. The apo-H46R structure exhibits partial disorder in the electrostatic and zinc loop elements in three of the four dimers in the asymmetric unit, while the fourth has ordered loops due to crystal packing interactions. In both structures, nonnative SOD1–SOD1 interactions lead to the formation of higher-order filamentous arrays. The disordered loop elements may increase the likelihood of protein aggregation in vivo, either with other H46R molecules or with other critical cellular components. Importantly, the binding of zinc is not sufficient to prevent the formation of nonnative interactions between pathogenic H46R molecules. The increased tendency to aggregate, even in the presence of Zn, arising from the loss of the secondary bridge is consistent with the observation of an increased abundance of hyaline inclusions in spinal motor neurons and supporting cells in H46R SOD1 transgenic rats.
Keywords: copper-zinc superoxide dismutase; familial amyotrophic lateral sclerosis; ALS; amyloid; SOD1; H46R
Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041256705.
Reprint requests to: S. Samar Hasnain, CCLRC Daresbury Laboratory, Warrington, Cheshire, WA4 4AD, UK; e-mail: s.hasnain{at}dl.ac.uk; fax: +44-1925-603748; or P. John Hart, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA; e-mail: pjhart{at}biochem.uthscsa.edu; fax: (210) 567-6596.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  X. Cao, S. V. Antonyuk, S. V. Seetharaman, L. J. Whitson, A. B. Taylor, S. P. Holloway, R. W. Strange, P. A. Doucette, J. S. Valentine, A. Tiwari, et al. Structures of the G85R Variant of SOD1 in Familial Amyotrophic Lateral Sclerosis J. Biol. Chem., June 6, 2008; 283(23): 16169 - 16177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dong, J. M. Canfield, A. K. Mehta, J. E. Shokes, B. Tian, W. S. Childers, J. A. Simmons, Z. Mao, R. A. Scott, K. Warncke, et al. Engineering metal ion coordination to regulate amyloid fibril assembly and toxicity PNAS, August 14, 2007; 104(33): 13313 - 13318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. W. Strange, C. W. Yong, W. Smith, and S. S. Hasnain Molecular dynamics using atomic-resolution structure reveal structural fluctuations that may lead to polymerization of human Cu Zn superoxide dismutase PNAS, June 12, 2007; 104(24): 10040 - 10044. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wang, A. Caruano-Yzermans, A. Rodriguez, J. P. Scheurmann, H. H. Slunt, X. Cao, J. Gitlin, P. J. Hart, and D. R. Borchelt Disease-associated Mutations at Copper Ligand Histidine Residues of Superoxide Dismutase 1 Diminish the Binding of Copper and Compromise Dimer Stability J. Biol. Chem., January 5, 2007; 282(1): 345 - 352. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Carroll, C. E. Outten, J. B. Proescher, L. Rosenfeld, W. H. Watson, L. J. Whitson, P. J. Hart, L. T. Jensen, and V. C. Culotta The Effects of Glutaredoxin and Copper Activation Pathways on the Disulfide and Stability of Cu,Zn Superoxide Dismutase J. Biol. Chem., September 29, 2006; 281(39): 28648 - 28656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ferri, M. Cozzolino, C. Crosio, M. Nencini, A. Casciati, E. B. Gralla, G. Rotilio, J. S. Valentine, and M. T. Carri Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials PNAS, September 12, 2006; 103(37): 13860 - 13865. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Banci, I. Bertini, F. Cantini, N. D'Amelio, and E. Gaggelli Human SOD1 before Harboring the Catalytic Metal: SOLUTION STRUCTURE OF COPPER-DEPLETED, DISULFIDE-REDUCED FORM J. Biol. Chem., January 27, 2006; 281(4): 2333 - 2337. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Lin, J. Zhai, and W. W. Schlaepfer RNA-binding protein is involved in aggregation of light neurofilament protein and is implicated in the pathogenesis of motor neuron degeneration Hum. Mol. Genet., December 1, 2005; 14(23): 3643 - 3659. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Banci, I. Bertini, N. D'Amelio, E. Gaggelli, E. Libralesso, I. Matecko, P. Turano, and J. S. Valentine Fully Metallated S134N Cu,Zn-Superoxide Dismutase Displays Abnormal Mobility and Intermolecular Contacts in Solution J. Biol. Chem., October 28, 2005; 280(43): 35815 - 35821. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
