Modifications to amino acids in sperm could be behind infertility

Sperm cells play a crucial role in the process of reproduction by delivering half of the genetic material needed for creating new life.

The success of this reproductive process relies on the development of functionally competent sperm cells, which are often determined by their shape. In cases of in vitro fertilization, the selection of the “best-looking” sperm is prioritized for fertilizing an egg.

However, assessing how the optimal sperm shape translates into proper sperm function is a challenging task due to various factors that can influence the results.

Researchers at the University of Michigan have now undertaken a molecular-level study of sperm formation, with a specific focus on understanding how abnormalities in this process can lead to male-factor infertility.

Unlike other cells in the body, sperm cells have a unique characteristic—their genetic material is packaged with proteins called protamines.

Protamines have been found in various living organisms, including plants, fish, and mammals, spanning millions of years of evolution.

This raises an intriguing question: why do sperm cells use protamines to package DNA instead of histones, which are used by all other cell types?

To uncover the significance of protamines in reproduction, a team of researchers conducted an in-depth study of the molecular sequence composition of protamines to understand how variations in the protein affect their function.

“We began studying protamines because they exist in many animal species and are rapidly evolving, resulting in a lot of sequence variation,” said Saher Sue Hammoud, Ph.D., an associate professor at the University of Michigan.

Mammals typically have multiple types of protamines that need to be maintained in the correct ratio, as deviations in this ratio have been linked to infertility.

Previous research suggests that protamines are efficient at tightly packaging DNA into structures called chromatin due to their high arginine content, as arginine strongly binds to DNA.

However, recent studies have revealed that protamines also contain non-arginine amino acids that are specific to each species and undergo unexpected post-translational modifications.

A study published in the journal Nature Structural & Molecular Biology explores previously unrecognized features of protamines.

“The molecules responsible for interacting with and packaging DNA are known to have positively charged features. What’s remarkable about this work is that it reveals other important functions performed by different amino acids in these proteins,” said Sy Redding, Ph.D., an assistant professor at the University of Massachusetts Chan Medical School.

Additionally, the presence of post-translational modifications on protamines, despite the transcriptionally inactive state of sperm cells, was found to be intriguing.

“The fact that protamines have these various modifications suggests that these modifications must serve a purpose in chromatin packaging,” said Lindsay Moritz, Ph.D., a postdoctoral fellow in the Hammoud Lab.

Using mice, the researchers analyzed a modified lysine residue specific to a mouse protamine, which is present in mature mouse sperm. Replacing lysine with an unmodifiable amino acid resulted in abnormally shaped sperm, impaired embryonic development, and reduced fertility.

Furthermore, replacing lysine with a positively charged arginine did not correct the defective sperm packaging, indicating that the interactions go beyond the charge of the molecule.

Male-factor infertility often lacks a clear cause, highlighting the importance of studying these modifications.

“I think these modifications are interesting as another avenue of research for identifying the cause of infertility. The fact that they might play a role in the early embryo has significant implications as a potential diagnostic tool and for post-fertilization processes in IVF,” noted Samantha Schon, M.D., assistant professor at the U-M Department of Obstetrics and Gynecology.

The research team aims to further investigate the mechanisms of sperm cell packaging in order to fully understand the process and potentially recreate it in vitro.

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