For the newly formed sperm, it has no motility and does not know where it will go in the future
Only when they reach the endometrium, under the action of capacitation factors, secretions, etc.
In this process, CatSper (The cation channel of sperm), a cation channel complex that is only distributed in sperm, plays a key role
On July 5, "Nature" published online the research results of Wu Jianping, a distinguished researcher of the School of Life Sciences of West Lake University.
CatSper: an important switch for sperm activation
CatSper: an important switch for sperm activation According to statistics from the World Health Organization, infertility affects as many as 186 million people and is a global public health problem
Although assisted reproductive technology has been widely used, there are still many biological problems in this field that need to be solved due to the lack of in-depth research on the mechanism of the fertilization process
In many infertile men, the expression of CatSper is significantly reduced, and the mutant of CATSPER2 (a component of CatSper) can also cause asthenospermia
Therefore, CatSper, a complex that was identified more than 20 years ago, has always been an important target for the treatment of male infertility and the development of new non-hormonal contraceptives
Mouse sperm under a fluorescence microscope, CatSper distributed in the red section, courtesy of Wu Jianping
The usual ion channel consists of a core component responsible for the transport of ions, and the slightly more complicated channel will have some auxiliary subunits, usually no more than five
It is precisely its uniqueness that aroused the interest of Wu Jianping, a researcher in the School of Life Sciences of West Lake University
Yan Ning, a professor at Princeton University in the United States, told the China Science News: “CatSper is a topic that many'successful' scientific research teams in the world are focusing on
The structure resembles a "jellyfish"
The structure resembles a "jellyfish" The multiple components of CatSper are entangled and stacked together to form a channel for ion transport
The first step of the experiment is purification, which separates CatSper from other proteins and non-protein molecules
After analysis and research, Wu Jianping’s team found a new way to find a set of "endogenous purification" strategies, "the equivalent of the traditional method is to use cells to replicate CatSper, and we take the ready-made CatSper directly from mouse sperm
"This should be the first time at the animal level that gene editing methods have been used to knock-in genes with affinity tags, so as to obtain complex complexes for structural analysis
Then, the team used single-particle three-dimensional reconstruction technology to analyze the structure of the mouse-derived CatSper protein cryo-EM with a resolution of 2.
9 angstroms, revealing the assembly method of the CatSper complex for the first time
.
CatSper whole cryo-electron microscope structure diagram is taken from the paper
The three-dimensional reconstruction image shows that the components of the CatSper channel body overlap and surround, resembling a "jellyfish", with a large "head" exposed outside the sperm cell membrane, the waist part inserted in the middle of the cell membrane, and several thin "legs" "Deep into the cell
.
Inside the "Jellyfish", the four main functional units of CatSper surround the channel area
.
"The channel region of CatSper consists of 4 completely different polypeptide chains, which has never been discovered in other ion channel studies,
" said Wu Jianping
.
After analyzing the known components of CatSper, he also found that there is excess density in the surrounding area of the electron microscope density.
"I am very happy to see these.
This shows that in addition to the 10 known components, CatSper still exists.
New unknown component
.
"
"Unexpected joy" in the experiment
"Unexpected joy" in the experiment How to determine the identity of these new unknown components?
Combined with methods such as mass spectrometry identification and protein structure prediction, the team members passed through one-by-one comparison and screening from hundreds of candidate proteins, and finally identified 3 brand-new components
.
What surprised them most was that one of the components turned out to be a transporter SLCO6C1
.
"Seeing its shape, it felt like a transporter at first, because I had done relevant structural studies before and I was very familiar with it
.
But I was puzzled.
After all, a transporter and an ion channel have never been encountered before
.
" He said
.
"I am very emotional, how could there be such a miraculous thing
.
" Wu Jianping told the China Science Daily, "The role of ion channels is to permeate ions, and the role of transporters is to transport small molecules.
Although they are the same cell membrane proteins, they are different from each other.
Coherent.
The
CatSper channel body contains both.
This not only refreshes people's understanding of the composition of CatSper, but also subverts the traditional concept of ion channels and transporters fighting each other in the cell
.
"
He said, "Our research reveals the unique assembly method of CatSper channel bodies for the first time, and provides in-depth mechanism explanations for understanding its functional regulation, ion transport and other processes.
It also provides insights
for subsequent infertility-related drugs and drugs based on the structure of CatSper channel bodies.
The foundation has been laid for the development of non-hormonal contraceptives
.
"
"I really didn't expect that in just one and a half years, and under the impact of the epidemic, the Jianping research team made this important breakthrough
.
" Yan Ning said, "This research expands the prospects for the functional research of CatSper.
Research methods may also become one of the mainstream methods of structural biology in the future
.
” (Source: Liu Runan, Chinese Journal of Science)
Related paper information: https:// href="https://doi.
org/10.
1038/s41586-021-03742-6" style="text-indent: 2em;" target="_blank">https://
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