Science: Big progress! Discover ACTMAP, a mysterious gene that matures actin, the main component of the cytoskeleton, ---

In a new study, Dutch Cancer Institute geneticist Thijn Brummelkamp and his team tracked down a "mystery gene": the gene ACTMAP
, which ensures actin production in its final form.

Thijn Brummelkamp, a geneticist at the Netherlands Cancer Institute, replied when asked why he excelled at tracking proteins and genes that no one else had found, "I'm very good at finding a needle in a haystack," even though some proteins and genes remained elusive
for up to 40 years.

In a new study, Brummelkamp and his team have once again succeeded in tracking down one of these "mystery genes": the gene
that ensures the production of actin in its final form.
The results of the study were published in the September 30, 2022 issue of the journal Science in the paper "Actin maturation requires the ACTMAP/C19orf54 protease"
.

Cell biologists are very interested in actin because actin--- a protein we produce more than 100 kilograms in our lifetime--- is a major component of the cytoskeleton and one of
the most abundant molecules in cells.
A large amount of actin can be found in every cell type, and it has many uses: it gives cells shape and makes them stronger; It plays an important role in cell division; It pushes cells forward and provides strength
to our muscles.

People with actin problems often suffer from muscle disease
.
A lot is known about the function of actin, but how is the final form of this important protein formed, and which gene is behind it? Brummelkamp said, "We don't know
.
”

Genetics in haploid human cells

Over the course of his career, Brummelkamp has developed a number of unique methods for this, which enabled him to conduct the first large-scale genetic study
of gene inactivation in human cells two decades ago.
"You can't cross people like fruit flies and see what happens
.
"

Brummelkamp and his team have been working with haploid human cells since 2009--- each gene contains only one copy instead of two (one copy from your father and one from your mother).

While the combination of two gene copies forms the basis of our entire existence, it also makes unnecessary noise when conducting genetic experiments, because mutations usually occur in only one copy of the gene (e.
g.
, the one from your father) and not the other
.

Together with other researchers, Brummelkamp uses this versatile approach to finding genetic causes
of specific diseases.
He has shown how Ebola and some other viruses, as well as certain forms of chemotherapy drugs
, get into cells.
He also studied why cancer cells are resistant to certain types of treatments and discovered a protein
found in cancer cells that brakes the immune system.
This time, he went looking for a gene
that matured actin.

Look for molecular scissors

As Brummelkamp's team describes in the journal Science, a protein usually has to be removed before it can fully function in the cell
.
This amino acid is then cut from the protein by a pair of molecular scissors
.
This is also the case
that occurs in actin.
It is known that this associated amino acid--- N-terminal acetylated methionine --- is cut off on which side of actin
.
However, no one has succeeded in finding an enzyme
that acts as molecular scissors in this process.

Peter Haahr, a postdoc in Brummelkamp's team, conducted the following experiment: First, he introduced random mutations (errors)
in random haploid cells.
He then selects cells containing immature actin by adding fluorescently labeled antibodies to these cells, which bind exactly where
the amino acid was removed.
As a third and final step, he studied which gene was mutated
after this process.

They call it "ACTMAP.
"

Then came an ecstatic moment: Haahr tracked down the molecular scissors that cut the essential amino acid from actin
.
The molecular scissors turned out to be controlled
by a gene whose function was previously unknown and no one had studied before.
This meant that the Brummelkamp team was able to name the gene themselves, which they named ACTMAP (ACTin MAturation Protease).

TO TEST WHETHER A DEFICIENCY IN ACTMAP CAUSED PROBLEMS IN THE ORGANISM, THEY TURNED OFF THE GENE
IN MICE.
They observed that actin in the cytoskeleton of these mice was still immature, as expected
.
They were surprised to find that the mice did survive, but suffered muscle weakness
.

ACTMAP is not the first mysterious gene
discovered by Brummelkamp that plays a role in our cytoskeletal function.
Using the same method, his team has been able to detect three unknown molecular scissors in recent years (Nature Structural & Molecular Biology, 2019, doi:10.
1038/s41594-019-0254-6): tubulin carboxypeptidase, VASH1, and SVBP, They cut off an amino acid
called tyrosine from another major component of the cytoskeleton--- tubulin---.
These molecular scissors allow tubulin to perform its dynamic function
normally within the cell.
They discovered in the journal Science in May this year that molecular scissors MATCAP is a microtubule-binding protease that detyrosines α-tubulin (Science, 2022, doi:10.
1126/science.
abn6020, see BioValley News report: Science: Major Progress!).
A new tubulin destyrosinase ---MATCAP)
was discovered.
Through early work on the cytoskeleton, Brummelkamp eventually targeted actin
.

Tubulin detyrosination is performed
by different MATCAP and vasohibin detyrosinase.
Image from Science, 2022, doi:10.
1126/science.
abn6020
.

Task: Map all 23,000 genes

Brummelkamp said, "Unfortunately, our new findings about actin don't tell us how to treat certain muscle diseases
.
But we provide new basics about the cytoskeleton that may later be useful to
others.
”

In addition, Brummelkamp's mission is to one day map the function of all 23,000 of our genes, and he can tick off another gene
from his huge list.
After all, we don't know what half of our genes do, which means we can't intervene
when something goes wrong.
(Bio Valley Bioon.
com)

Resources:

1.
Peter Haahr et al.
 Actin maturation requires the ACTMAP/C19orf54 protease.
Science, 2022, doi:10.
1126/science.
abq5082.

2.
'Mystery gene' matures the skeleton of the cell

https://phys.
org/news/2022-09-mystery-gene-matures-skeleton-cell.
html