ESRF News March 2024

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March 2024 ESRFnews

C E L L 1 8 7 6 9 2 E S R F/M A X I M B Y K O V

Structure reveals protein cooperation

behind facial appearance

Researchers led by a group at Stanford

University in the US have found that

two types of transcription factors,

which contribute to individual

differences in facial appearance, work

together during the development of

human embryos. The scientists solved

the structures of the TWIST1 and

homeodomain proteins in complex

with DNA at the ESRF beamline

ID23-1.

Transcription factors (TFs) are

proteins that can turn genes on or off.

In humans, large families of TFs, such

as the homeodomain (HD) and basic

helix-loop-helix (bHLH) proteins,

play roles in shaping cellular and

positional identities during embryonic

development. TWIST1 is part of the

bHLH family, and plays a crucial part

in the formation of tissues and organs,

including the development of the

skeleton and muscles.

To bind to DNA in a precise way,

and ensure gene control, TFs from

these large families often collaborate,

a process known as cooperative TF

binding. While there are various

ways TFs can cooperate, one less

understood method, DNA-mediated

cooperativity, involves TFs binding

to neighbouring DNA sites without

directly interacting with each

other. This has been observed in lab

experiments, but its detailed study

in living cells is limited to a few

examples.

Now the Stanford-led team has

studied TWIST1 and its binding

to homeodomain TFs and DNA. In

collaboration with ESRF scientist

Sasha Popov, the researchers have

used ID23-1 to solve the X-ray

crystal structure of TWIST1, its

heterodimerisation partner TCF4,

and homeodomain factor ALX4

co-bound at a specific DNA sequence.

The researchers found that when

TWIST1 and ALX4 team up, they

enhance the ability of certain regions

in the DNA to be accessed, resulting in

gene activation. They also discovered

that the connections between

TWIST1 and homeodomain TFs are

weak, yet stabilised by the DNA. This

weak interaction helps in the selective

choice of partners, and therefore allows

a shared control over transcription in

specialised embryonic cell types that

give rise to the limbs and facial features

(Cell 187 692).

“This research shows how a

cooperation guided by DNA can be

highly selective among members of

large TF families, in turn resulting in

exquisite regulatory specificity that

ultimately shapes facial morphology

and evolution,” says Stanford’s

Joanna Wysocka, the leading scientist

of the study.

‘Guanidinate’ anion

synthesised

Three ESRF beamlines have probed

the first compounds containing a

new “guanidinate” anion. The anion

expands the family of carbon-nitrogen

inorganic anions, and holds promise for

optical technologies.

Inorganic ternary metal-C-N

compounds with covalently bonded

C-N anions are a significant class

of solids with diverse applications.

Among these compounds, cyanides

(CN

) and carbodiimides (CN

) are

extensively studied and used in various

fields. However, the next member of the

series – the CN

anion, a completely

deprotonated guanidine molecule

– has remained elusive, despite

numerous attempts to synthesise it

using strong bases to deprotonate

guanidine molecules.

In a recent breakthrough, research

teams from the University of Bayreuth,

the University of Cologne and Goethe

University Frankfurt in Germany

have successfully synthesised the

first representatives of the CN

-containing guanidinates and

oxo-guanidinates, via solid-state

synthesis under extreme conditions

in laser-heated diamond anvil cells.

At ID27 and ID15B they conducted

pressure-dependent single-crystal

X-ray diffraction to elucidate the crystal

structures and properties, while

X-ray absorption near-edge structure

spectroscopy at ID12 allowed them

to confirm one of the key oxidation

states (Angew. Chem. Int. Ed. 62

e202311516; e202311519).

Despite their highpressure

synthesis the compounds remained

stable at ambient conditions

suggesting potential for various

applications One of the new

compounds SbCN

exhibits direct

bandgap semiconductor properties

making it a candidate for optical

devices Other guanidinates and

orthonitridocarbonates could

prove useful for enhanced

photochemical watersplitting and

nonlinear optical devices

The structure of

TWIST1, TCF4 and

ALX4 DNA-binding

domains bound to

the coordinator

DNA sequence,

as revealed by

ID23-1 data.