Meddling with metals: Escaping the tyranny of copper
Flexible system sidesteps copper-protein binding

Date:
March 4, 2022
Source:
University of California - San Diego
Summary:
Researchers have reported a new protein-design strategy to sidestep
the Irving-Williams Series, allowing proteins to behind to other
metals ahead of copper.



FULL STORY ==========================================================================
It may seem counterintuitive to many, but metal ions play a critical
role in life, carrying out some of the most important biological
processes. Think of hemoglobin -- a metalloprotein responsible for
carrying oxygen to the body's organs via red blood cells. Metalloproteins
are proteins bound by at least one metal ion. In the case of hemoglobin,
that metal is iron.


==========================================================================
For metalloproteins to work properly, they must be paired with the correct metal ion -- hemoglobin can only function with iron Yet, protein-metal
binding is normally governed by a strict order, called the Irving-Williams Series, which dictates that copper ions should bind to proteins over
other metals.

In other words, if a cell contained equal amounts of different metal
ions, most cellular proteins and other components would bind to copper, clogging up cellular machinery in the process. This is why organisms
spend considerable energy keeping very strict controls over how much
free copper is present in cells.

Now researchers in the University of California San Diego's Division of Physical Sciences have reported a new protein-design strategy to sidestep
the Irving-Williams Series. The findings were published earlier this
week in the journal Nature.

Professor of Chemistry and Biochemistry Akif Tezcan and postdoctoral
scholar Tae Su Choi designed a flexible protein that selectively binds
other metal ions over copper, paving the way for the design of novel
functional proteins and metal sequestration agents. Choi and Tezcan
discovered that selective binding to non-copper metals required the
artificial protein to present a very specific combination of amino acids
and geometries to discriminate against copper. This discovery required
an uncommon design approach.

"Protein design typically involves trying to craft a discrete protein
structure that can perform a certain function, such as catalysis. This
approach is inherently deterministic and follows the sequence of one
design-one structure- one function," stated Tezcan. "Best case scenario,
you obtain the structure and function that is designed. However,
this approach doesn't leave much room for the discovery of new design principles or unexpected outcomes, which are potentially more significant
than what was originally planned." Tezcan and Choi took a probabilistic approach instead. At the outset, their designed protein wasn't engineered
to possess a singular structure that selectively binds to a certain type
of metal. They created a flexible system that could arrange itself in
multiple ways to bind different metal ions in different geometries. It
was this flexibility that led them to an outcome they did not originally
plan for.

"In analyzing these systems, we saw that proteins were binding to
cobalt and nickel ions ahead of copper, which is not the natural order
of things," stated Choi. "We created an hypothesis and tested new
variants. After extensive analysis, we realized we could construct a
protein environment where copper was disfavored." "This is an example of designing a pathway rather that a target," explained Tezcan. "I personally think that this is a more exciting way to go about the protein design
problem. By incorporating an element of flexibility into the design, we
leave open the possibility of different outcomes and new design principles
we couldn't have known beforehand." Research on selective metal binding
and protein design has importance beyond a better understanding of the fundamentals of life. It can also lay the foundation for more efficient processes during environmental remediation, such as when certain metals
need to be sequestered in contaminated water. Protein design is also a
critical part of pharmaceutical research and development.

"We were intrigued by the question 'Can we design proteins that
can selectively bind to metals or have catalytic reactions in
ways that evolution has not yet invented?'" said Choi. "Just
because biology doesn't do it, it doesn't mean it's not possible." ========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Michelle
Franklin. Note: Content may be edited for style and length.


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The_structure_of_the_designed_metalloprotein_with_selective_metal_binding
sites.

========================================================================== Journal Reference:
1. Tae Su Choi, F. Akif Tezcan. Overcoming universal restrictions
on metal
selectivity by protein design. Nature, 2022; DOI:
10.1038/s41586-022- 04469-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220304182939.htm

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