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hRad50.lyx
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hRad50.lyx
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#LyX 2.3 created this file. For more info see http://www.lyx.org/
\lyxformat 544
\begin_document
\begin_header
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\textclass classicthesis
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\begin_body
\begin_layout Chapter
Relations between Structure and Zn(II) Binding Affinity Shed Light on the
Mechanisms of Rad50 Hook Domain Functioning and Its Phosphorylation
\end_layout
\begin_layout Standard
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
chaptermark{
\backslash
protect
\backslash
parbox{0.9
\backslash
linewidth}{Relations between Structure and Zn(II) Binding Affinity Shed
Light on the Mechanisms of Rad50 Hook Domain Functioning and Its Phosphorylatio
n}}
\end_layout
\end_inset
\end_layout
\begin_layout Standard
\begin_inset CommandInset label
LatexCommand label
name "chap:hRad50"
\end_inset
\end_layout
\begin_layout Standard
\shape smallcaps
Józef Ba Tran, Michał Padjasek and Artur Krężel
\shape default
\begin_inset Newline newline
\end_inset
\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
\begin_inset Newline newline
\end_inset
\shape italic
International Journal of Molecular Sciences
\shape default
\size small
\size default
2022 23, 11140.
\begin_inset VSpace medskip
\end_inset
\end_layout
\begin_layout Section
Brief history and bibliometric data
\end_layout
\begin_layout Standard
My early work as a researcher of protein-metal interactions involved joint
work with Michał Padjasek on the Rad50 protein from
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{sc}
\end_layout
\end_inset
(data not published yet).
\begin_inset CommandInset citation
LatexCommand citep
key "Padjasek2022"
literal "true"
\end_inset
It was Michal Padjasek who largely showed me the ins and outs of the experiment
s that give insight into the world of
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{mprotein}
\end_layout
\end_inset
.
It was this knowledge that allowed me to study the behavior of the zinc
hook from the human
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
.
Historically, my participation in the research is part of a larger project,
already separated into several grants, devoted to studying the orthologs
of the zinc hook from
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
protein.
This research was initiated by Tomasz Kochańczyk and continued by Michał
Padjasek, myself, Olga Kerber, and Marek Łuczkowski.
As it turned out, the zinc hook from the human
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
behaves in a different way than its orthologs from
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{pf}
\end_layout
\end_inset
and
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{sc}
\end_layout
\end_inset
.
The hard work on this subject resulted in a publication in the
\shape italic
International Journal of Molecular Sciences
\emph on
, a journal with an
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{if}
\end_layout
\end_inset
of 6.208 (as of March 6, 2023)
\shape default
\emph default
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
begin{pycode}[sessionA]
\end_layout
\begin_layout Plain Layout
from scholarly import scholarly
\end_layout
\begin_layout Plain Layout
\end_layout
\begin_layout Plain Layout
\end_layout
\begin_layout Plain Layout
num2words = {1: 'one',
\end_layout
\begin_layout Plain Layout
2: 'two',
\end_layout
\begin_layout Plain Layout
3: 'three',
\end_layout
\begin_layout Plain Layout
4: 'four',
\end_layout
\begin_layout Plain Layout
5: 'five',
\end_layout
\begin_layout Plain Layout
6: 'six',
\end_layout
\begin_layout Plain Layout
7: 'seven',
\end_layout
\begin_layout Plain Layout
8: 'eight',
\end_layout
\begin_layout Plain Layout
9: 'nine',
\end_layout
\begin_layout Plain Layout
10: 'ten',
\end_layout
\begin_layout Plain Layout
11: 'eleven',
\end_layout
\begin_layout Plain Layout
12: 'twelve',
\end_layout
\begin_layout Plain Layout
13: 'thirteen',
\end_layout
\begin_layout Plain Layout
14: 'fourteen',
\end_layout
\begin_layout Plain Layout
15: 'fifteen',
\end_layout
\begin_layout Plain Layout
16: 'sixteen',
\end_layout
\begin_layout Plain Layout
17: 'seventeen',
\end_layout
\begin_layout Plain Layout
18: 'eighteen',
\end_layout
\begin_layout Plain Layout
19: 'nineteen',
\end_layout
\begin_layout Plain Layout
20: 'twenty',
\end_layout
\begin_layout Plain Layout
30: 'thirty',
\end_layout
\begin_layout Plain Layout
40: 'forty',
\end_layout
\begin_layout Plain Layout
50: 'fifty',
\end_layout
\begin_layout Plain Layout
60: 'sixty',
\end_layout
\begin_layout Plain Layout
70: 'seventy',
\end_layout
\begin_layout Plain Layout
80: 'eighty',
\end_layout
\begin_layout Plain Layout
90: 'ninety',
\end_layout
\begin_layout Plain Layout
0: 'zero'}
\end_layout
\begin_layout Plain Layout
\end_layout
\begin_layout Plain Layout
\end_layout
\begin_layout Plain Layout
def n2w(n):
\end_layout
\begin_layout Plain Layout
try:
\end_layout
\begin_layout Plain Layout
return (num2words[n])
\end_layout
\begin_layout Plain Layout
except KeyError:
\end_layout
\begin_layout Plain Layout
try:
\end_layout
\begin_layout Plain Layout
return ((num2words[n-n % 10]) + ' ' + (num2words[n % 10].lower()))
\end_layout
\begin_layout Plain Layout
except KeyError:
\end_layout
\begin_layout Plain Layout
return ('Number out of range')
\end_layout
\begin_layout Plain Layout
\end_layout
\begin_layout Plain Layout
\end_layout
\begin_layout Plain Layout
search_query = scholarly.search_single_pub(
\end_layout
\begin_layout Plain Layout
'Relations between Structure and Zn (II) Binding Affinity Shed Light
on the Mechanisms of Rad50 Hook Domain Functioning and Its Phosphorylation')
\end_layout
\begin_layout Plain Layout
\end_layout
\begin_layout Plain Layout
num_citations = search_query['num_citations']
\end_layout
\begin_layout Plain Layout
\end_layout
\begin_layout Plain Layout
if num_citations == 0:
\end_layout
\begin_layout Plain Layout
print(', and though the article was not cited yet (as of
\backslash
\backslash
today),
\backslash
\backslash
footnote{
\backslash
\backslash
url{https://scholar.google.com/}} it gives a solid foundation for the discussion
of unique properties of the zinc hook from
\backslash
\backslash
gls{sc}
\backslash
\backslash
gls{rad}.')
\end_layout
\begin_layout Plain Layout
elif num_citations > 0:
\end_layout
\begin_layout Plain Layout
if num_citations <= 10:
\end_layout
\begin_layout Plain Layout
print(f'.
The article was cited by {n2w(num_citations)} other articles so far (as
of
\backslash
\backslash
today).')
\end_layout
\begin_layout Plain Layout
else:
\end_layout
\begin_layout Plain Layout
print(f'.
The article was cited by {num_citations} other articles so far (as of
\backslash
\backslash
today).''
\backslash
\backslash
footnote{
\backslash
\backslash
url{https://scholar.google.com/}}')
\end_layout
\begin_layout Plain Layout
\end_layout
\begin_layout Plain Layout
\backslash
end{pycode}
\end_layout
\begin_layout Plain Layout
\end_layout
\end_inset
\end_layout
\begin_layout Section
Summary
\end_layout
\begin_layout Standard
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
Glspl{ppi}
\end_layout
\end_inset
play a crucial role in many biological processes and are usually stabilized
by an extensive network of non-covalent intermolecular interactions.
An additional factor contributing to the formation of protein complexes
is intermolecular metal binding, in which the affinity of the metal for
the protein affects the stability of the entire complex.
Most of the metal-involved
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{ppi}
\end_layout
\end_inset
are uncharacterized in terms of the role of metal at the interface or in
terms of the complex stability.
One of few, quite well characterized
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{zppi}
\end_layout
\end_inset
is the interaction observed in the zinc hook domain of the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
.
Zn(II)-
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
complex.
Previous studies have investigated the relationship between the structure
of the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{pf}
\end_layout
\end_inset
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
and Zn(II)-complex stability.
\begin_inset CommandInset citation
LatexCommand citep
key "Kochanczyk2016,Kochanczyk2016a,Padjasek2020a"
literal "true"
\end_inset
Those studies show that the complex stabilization occurs primarily in a
small 45-amino-acid-long fragment consisting of the CXXC
\begin_inset Note Note
status open
\begin_layout Plain Layout
możliwe, że trzeba wytłumaczyć wcześniej czym jest ten CXXC motif.
\end_layout
\end_inset
binding motif and the flanking region.
In
\begin_inset CommandInset citation
LatexCommand citebyear
key "Park2017"
literal "true"
\end_inset
publication appeared that shifted the paradigm about the architecture of
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
.
\begin_inset CommandInset citation
LatexCommand citep
key "Park2017"
literal "true"
\end_inset
The newly published structure (
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{pdb}
\end_layout
\end_inset
5GOX) presented the rod-shape of the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{hs}
\end_layout
\end_inset
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
, and as it usually is with new data, new questions arise.
How does the rod-shaped architecture of
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
determines the complex stability? What are the elements that contribute
to the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
stability? Are there any other factors that influence the formation and
the complex stability?
\end_layout
\begin_layout Standard
We have hypothesized that increasing the length of the peptides being studies,
similarly to
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{pf}
\end_layout
\end_inset
Rad50
\begin_inset CommandInset citation
LatexCommand citep
key "Kochanczyk2016a"
literal "true"
\end_inset
, would increase the stability of the complex by increasing the number of
inter- and intra- interactions.
To test this hypothesis we used potentiometry and competition titration
with spectropolarimetric detection.
The results showed that in contrast to
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
from
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{pf}
\end_layout
\end_inset
the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{hs}
\end_layout
\end_inset
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
Zn(II)-complex stabilization occurs over much longer distance.
The observation we have made show that the human
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
forms the strongest known Zn(II)-protein known so far.
This extremely elevated stability is due to similar effect that was observed
in the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{pf}
\end_layout
\end_inset
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
– However, the extent of the effect in human
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
is much greater, the stabilization occurs over the length of 140 amino-acids,