Abstract
Zinc (II) ions (hereafter simplified as zinc) are important for the structural and functional activity of many proteins. For Cu, Zn superoxide dismutase (Sod1), zinc stabilizes the native structure of each Sod1 monomer, promotes homo-dimerization and plays an important role in activity by “softening” the active site so that copper cycling between Cu(I) and Cu(II) can rapidly occur. Previously, we have reported that binding of Sod1 by its copper chaperone (Ccs) stabilizes a conformation of Sod1 that promotes site-specific high-affinity zinc binding. While there are a multitude of Sod1 mutations linked to the familial form of amyotrophic lateral sclerosis (fALS), characterizations by multiple research groups have been unable to realize strong commonalities among mutants. Here, we examine a set of fALS-linked Sod1 mutations that have been well-characterized and are known to possess variation in their biophysical characteristics. The zinc affinities of these mutants are evaluated here for the first time and then compared with the previously established value for wild-type Sod1 zinc affinity. Ccs does not have the same ability to promote zinc binding to these mutants as it does for the wild-type version of Sod1. Our data provides a deeper look into how (non)productive Sod1 maturation by Ccs may link a diverse set of fALS-Sod1 mutations.
Highlights
Zinc ions are essential trace metals necessary for life
Aberrant zinc binding of form of amyotrophic lateral sclerosis (fALS)-Sod1 mutants has been a topic of much speculation, but little direct evidence for this notion has been provided by the field
We showed that wt-Sod1 binds zinc with a very tight affinity compared to other known zinc binding proteins and that interaction copper chaperone for Sod1 (Ccs) stabilizes site-specific zinc binding by immature Sod1 [16]
Summary
Zinc plays an important structural role in many proteins needed for cell function [1] and there are families of enzymes that use zinc as a catalytic cofactor [2,3]. It is not well understood how proteins acquire zinc. Zinc transporters are responsible for importing the ion into the cell and moving it to intracellular compartments such as the endoplasmic reticulum, golgi or nucleus where many proteins requiring zinc are metallated [4]. Sod catalyzes the dismutation of superoxide; turning superoxide radical into water and hydrogen peroxide in a two-step
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