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#Chapter04.lyx#
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#Chapter04.lyx#
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#LyX 2.3 created this file. For more info see http://www.lyx.org/
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\begin_body
\begin_layout Chapter
Galvanization of Protein-Protein Interactions in a Dynamic Zinc Interactome
\end_layout
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\backslash
chaptermark{
\backslash
protect
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parbox{0.9
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linewidth}{Galvanization of Protein-Protein Interactions in a Dynamic Zinc
Interactome}}
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\begin_inset CommandInset label
LatexCommand label
name "chap:Galvanization-of-Protein-Protein"
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\begin_layout Standard
\shape smallcaps
Anna Kocyła, Józef Ba Tran and Artur Krężel
\shape default
\begin_inset Newline newline
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\begin_inset Flex CT - Spaced Low Small Caps
status open
\begin_layout Plain Layout
Department of Chemical Biology, Faculty of Biotechnology University of Wrocław,
F.
Joliot-Curie 14a, 50-383 Wrocław, Poland
\end_layout
\end_inset
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Trends in Biochemical Sciences
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2021 46(1), 64–79.
\begin_inset VSpace medskip
\end_inset
\end_layout
\begin_layout Section
Brief history and bibliometric data
\end_layout
\begin_layout Standard
Something
\end_layout
\begin_layout Section
Summary
\end_layout
\begin_layout Standard
The functions that are performed by macromolecules in the cell are dependent
on the interaction with their partners.
What is the partner of the interaction depends on the role of the macromolecule.
For example, in the case of glucose-6-phosphate isomerase the one of the
interaction partners for the enzyme is glucose 6-phosphate, which is interconve
rted into fructose-6-phosphate.
\begin_inset CommandInset citation
LatexCommand citep
key "Berg2007"
literal "true"
\end_inset
Other proteins interact with lipids, nucleic acid and other proteins.
It is not an exaggeration to state that virtually every protein have to
interact, transiently or permanently, with other macromolecules to realize
its function in the organism.
The holistic knowledge
\begin_inset Note Note
status open
\begin_layout Plain Layout
nie wiem czy tutaj dobrze używam holistyczny
\end_layout
\end_inset
about these interactions is used to plot the map of the interactions, which
in turn can identify the functions of the proteins and their interdependence
leading to understanding the cellular function.
\begin_inset CommandInset citation
LatexCommand citep
key "Cafarelli2017"
literal "true"
\end_inset
From this network of interactions,
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{ppi}
\end_layout
\end_inset
are crucial to gain comprehension about the functional relationships between
proteins.
Over the last decades, the development of
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{hts}
\end_layout
\end_inset
methods e.g.
peptide phage display
\begin_inset CommandInset citation
LatexCommand citep
key "Sundell2014"
literal "true"
\end_inset
, yeast surface display
\begin_inset CommandInset citation
LatexCommand citep
key "Boder1997"
literal "true"
\end_inset
, yeast-two-hybrid system
\begin_inset CommandInset citation
LatexCommand citep
key "Fields1989"
literal "true"
\end_inset
and others lead to heaping amount of data.
Together with huge amount of data a large number of databases have been
founded to curate and annotate the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{ppi}
\end_layout
\end_inset
.
\begin_inset CommandInset citation
LatexCommand citep
key "Patil2018"
literal "true"
\end_inset
\end_layout
\begin_layout Standard
However, none of the vast interaction networks presents full landscape,
as interactions induced by small ligands as well as caused by metal ions
may be missing from the picture.
What is worth mentioning here, is the rough projection of how many proteins
associate with metal ions – it is estimated that roughly 30-40% of all
proteins interact with metal ions.
\begin_inset CommandInset citation
LatexCommand citep
key "Andreini2008,Andreini2013,Waldron2009"
literal "true"
\end_inset
Taking into account that bioinformatic analyses estimate that in human
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{proteome}
\end_layout
\end_inset
every tenth protein is a zinc-binding protein
\begin_inset CommandInset citation
LatexCommand citep
key "Andreini2009,Bertini2010"
literal "true"
\end_inset
, and the fact that most of the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{hts}
\end_layout
\end_inset
methods do not even consider the presence of another actors (i.e.
Zn(II)) in the interaction, thus causing such interactions to be overlooked,
makes a substantial amount of interactions not fully resolved.
\begin_inset Note Note
status open
\begin_layout Plain Layout
nie wiem czy resolved jest dobrym słowem tutaj.
\end_layout
\begin_layout Plain Layout
W ogóle to zdanie jest średnie i może wymagać zmiany
\end_layout
\end_inset
Though metal ions, compared to macromolecules, are small, compared both,
mass and dimensions, they have a significant impact on the structure of
the protein implying the consequences for the stability and function of
protein, and protein complexes.
Though the impact of the of various metal ions on the living organisms
have been studied for a while, and the effects of deficit or surplus of
some microelements are known, the mechanism of action of those elements
may be still vague.
As have been described in
\begin_inset Flex CT - auto cross-reference
status open
\begin_layout Plain Layout
\begin_inset CommandInset ref
LatexCommand labelonly
reference "ch:Zn(II) binding sites"
plural "false"
caps "false"
noprefix "false"
\end_inset
\end_layout
\end_inset
Zn(II) can be found in various architectures.
The studies how the architecture translates into function led to identification
of catalytic and structural zinc-binding sites, however the fact that Zn(II)
can in be located on the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{interface}
\end_layout
\end_inset
is often overlooked.
\begin_inset Note Note
status open
\begin_layout Plain Layout
W tym paragrafie szybko opisać dlaczego cynk.
\end_layout
\end_inset
\end_layout
\begin_layout Standard
Our goal in this report was to provide a comprehensive description of
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{zppi}
\end_layout
\end_inset
.
We wanted to underline that the presence of Zn(II) at protein-protein
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{interface}
\end_layout
\end_inset
plays a role in orchestrating the complex stability, adds additional level
of the protein complex regulation, and despite the fact that it seems to
be quite a rare phenomenon the presence of Zn(II) is crucial for fulfilling
several essential for the organism physiological functions.
As a showcase example
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{cry}
\end_layout
\end_inset
/
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{per}
\end_layout
\end_inset
Zn(II)–protein complex, essential component of the circadian clock, can
be evoked, where interdependent Zn(II) complexation and disulfide bond
formation modulates the complex.
\begin_inset CommandInset citation
LatexCommand citep
key "Schmalen2014"
literal "true"
\end_inset
Our review article, attached bellow presents more fascinating
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{zppi}
\end_layout
\end_inset
examples where Zn(II) is essential for proper functioning of the protein
complexes.
\end_layout
\begin_layout Standard
The description of outstanding
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{zppi}
\end_layout
\end_inset
examples is only one part of our review, the formation of
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{zppi}
\end_layout
\end_inset
is governed by the same thermodynamic and chemical principles as regular
protein-protein complexes, however the involvement of Zn(II) in the complexatio
n makes the formation of complex dependent on the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glslink{freezn}{Zn(II)
\backslash
textsubscript{free}}
\end_layout
\end_inset
.
This dependence of complex formation on an additional factor might be unclear,
thus to introduce the reader into the world of chemical equilibria we discuss
the effect of availability of the Zn(II) and its fluctuations caused by
Zn(II) influx and efflux, and its effect on formation of
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{zppi}
\end_layout
\end_inset
.
Because the mechanisms of action of various zinc transients are still unknown,
our contemplation on the subject is purely hypothetical, nevertheless,
we can deduce that
\emph on
terra incognita
\emph default
of Zn(II) fluctuations and the interdependence of
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{zppi}
\end_layout
\end_inset
formation
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{zppi}
\end_layout
\end_inset
is a vast, worth investigating field.
\end_layout
\begin_layout Standard
For sure the impact of the review would have been lower if no thorough survey
on
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{zppi}
\end_layout
\end_inset
was made.
I have decided to collect information about discovered protein-protein
complexes with Zn(II) on the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{interface}
\end_layout
\end_inset
.
So how does one search for
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{zppi}
\end_layout
\end_inset
? How common is zinc at protein-protein
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{interface}
\end_layout
\end_inset
?
\begin_inset Note Note
status open
\begin_layout Plain Layout
nwm czy to pytanie jest rozwiewane w zupełności
\end_layout
\end_inset
It is known that characteristic sequence motifs involving cysteines, histidines
and acidic residues
\begin_inset Foot
status open
\begin_layout Plain Layout
glutamates and aspartates
\end_layout
\end_inset
\begin_inset Marginal
status open
\begin_layout Plain Layout
Single-letter code for these amino acids and their frequency in Zn(II)-binding
sequences was an inspiration for the tool
\begin_inset Quotes eld
\end_inset
CHED
\begin_inset Quotes erd
\end_inset
.
\begin_inset Note Note
status open
\begin_layout Plain Layout
nie wiem czy tu poprawnie these używam.
\end_layout
\end_inset
\end_layout
\end_inset
that provide clue to Zn(II) coordination within single-chain protein.
Yet, the prediction, based solely on the protein sequence, of metal binding
on the protein-protein
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{interface}
\end_layout
\end_inset
to date is not possible.
One way of identification would be thorough literature search, one could
hypothetically search the Internet using research tools for scientific
literature like Google Scholar (
\begin_inset Flex URL
status open
\begin_layout Plain Layout
https://scholar.google.com/
\end_layout
\end_inset
), Semantic Scholar (
\begin_inset Flex URL
status open
\begin_layout Plain Layout
https://www.semanticscholar.org/
\end_layout
\end_inset
) or other similar tools utilizing keywords
\begin_inset Quotes eld
\end_inset
zinc
\begin_inset Quotes erd
\end_inset
,
\begin_inset Quotes eld
\end_inset
intermolecular binding
\begin_inset Quotes erd
\end_inset
,
\begin_inset Quotes eld
\end_inset
protein-protein
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{interface}
\end_layout
\end_inset
\begin_inset Quotes erd
\end_inset
.
However this way of analysis seems to be cumbersome, requires tremendous
amount of manual work, not to mention that the found literature might not
be available.
The only logical solution to the problem is to search online databases
that provide information about proteins.
Usually for the researcher the first source of information about protein
of interest is UniProt
\begin_inset CommandInset citation
LatexCommand citep
key "Bateman2022"
literal "true"
\end_inset
, significant amount of protein sequences aggregated in UniProt are properly
annotated to interact with metal ions, including Zn(II) ion, alas, UniProt
does not provide the information whether the metal ion is bound on the
protein-protein
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{interface}
\end_layout
\end_inset
.
Taking into account the fact of non-existence of metal ions at protein-protein
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{interface}
\end_layout
\end_inset
and the fact that it is not possible (so far) infer the intermolecular
binding based on the sequence solely I have decided to use one of the most
comprehensive resources available for any structural biologist – the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glsfirst{rcsb}
\end_layout
\end_inset
\begin_inset CommandInset citation
LatexCommand citep
key "Berman,Burley2021"
literal "true"
\end_inset
.
The reason why I used
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rcsb}
\end_layout
\end_inset
as a source of information, instead of already established databases containing
structures of metal ion-protein complexes (e.g.
MetalPDB
\begin_inset CommandInset citation
LatexCommand citep
key "Andreini2013"
literal "true"
\end_inset
, ZincBind
\begin_inset CommandInset citation
LatexCommand citep
key "Ireland2019"
literal "true"
\end_inset
) is shortly discussed in the review.
Using the data from
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rcsb}
\end_layout
\end_inset
and a simple
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{python}
\end_layout
\end_inset
scripts I was able to automate much of the required effort.
\end_layout
\begin_layout Standard
One of the biggest pitfalls of our work, as well similar studies (e.g.
\begin_inset CommandInset citation
LatexCommand citep
key "Laitaoja2013,Song2014"
literal "true"
\end_inset
), is the fact that the gathered knowledge simultaneously with the acceptance
of the article stops from being updated.
It does not mean it becomes automatically outdated, the extensive description
and analysis of the gathered and reviewed examples stays scientifically
true until the next breakthrough in the field, however the lists of structures,
and interwoven statistics and numbers change over time.
From the publication date of
\begin_inset CommandInset citation
LatexCommand citetitle
key "Kocyla2021"
literal "true"
\end_inset
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rcsb}
\end_layout
\end_inset
(accessed
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
today
\end_layout
\end_inset
) is richer with
\begin_inset ERT
status collapsed
\begin_layout Plain Layout
\backslash
begin{pycode}[sessionA]
\end_layout
\begin_layout Plain Layout
import json
\end_layout
\begin_layout Plain Layout
import requests
\end_layout
\begin_layout Plain Layout
from datetime import date
\end_layout
\begin_layout Plain Layout
\end_layout
\begin_layout Plain Layout
def fetch_PDB_Zn_codes(to_date):
\end_layout