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Sequence and structural determinants of Cu, Zn superoxide dismutase aggregation
Author(s) -
Khare Sagar D.,
Wilcox Kyle C.,
Gong Peng,
Dokholyan Nikolay V.
Publication year - 2005
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.20629
Subject(s) - protein aggregation , sod1 , sequence (biology) , chemistry , protein folding , superoxide dismutase , dimer , intermolecular force , context (archaeology) , protein structure , biophysics , biochemistry , biology , enzyme , molecule , paleontology , organic chemistry
Diverse point mutations in the enzyme Cu, Zn superoxide dismutase (SOD1) are linked to its aggregation in the familial form of the disease amyotrophic lateral sclerosis. The disease‐associated mutations are known to destabilize the protein, but the structural basis of the aggregation of the destabilized protein and the structure of aggregates are not well understood. Here, we investigate in silico the sequence and structural determinants of SOD1 aggregation: (1) We identify sequence fragments in SOD1 that have a high aggregation propensity, using only the sequence of SOD1, and (2) we perform molecular dynamics simulations of the SOD1 dimer folding and misfolding. In both cases, we identify identical regions of the protein as having high propensity to form intermolecular interactions. These regions correspond to the N‐ and C‐termini, and two crossover loops and two β‐strands in the Greek‐key native fold of SOD1. Our results suggest that the high aggregation propensity of mutant SOD1 may result from a synergy of two factors: the presence of highly amyloidogenic sequence fragments (“hot spots”), and the presence of these fragments in regions of the protein that are structurally most likely to form intermolecular contacts under destabilizing conditions. Therefore, we postulate that the balance between the self‐association of aggregation‐prone sequences and the specific structural context of these sequences in the native state determines the aggregation propensity of proteins. Proteins 2005. © 2005 Wiley‐Liss, Inc.