Sperm are vital for creating new life, carrying half of the genetic material needed to form a baby. The success of fertilization depends largely on sperm quality, which is often judged by its shape. In procedures like in vitro fertilization (IVF), technicians select the “best-looking” sperm to fertilize an egg. But how sperm shape relates to its actual function has been hard to understand because many factors come into play.
Researchers at the University of Michigan are now investigating sperm formation at the molecular level. They focus on how defects during this process might lead to male infertility.
What Makes Sperm DNA Packaging Unique?
Unlike other cells, sperm package their DNA using special proteins called protamines. These proteins are found across many species, including plants, fish, and mammals, and have existed for hundreds of millions of years.
This raises an important question: Why do sperm use protamines instead of histones, which are the proteins used by almost all other cells to package DNA?
To answer this, a team led by Saher Sue Hammoud, Ph.D., and colleagues studied the detailed molecular makeup of protamines. They wanted to see how changes in these proteins affect sperm function.
Most mammals have different types of protamines, and they must be kept in a precise balance. When this balance is off, infertility can result.
Beyond Just Packing DNA Tightly
It was long believed that protamines are effective because they contain lots of arginine, a positively charged amino acid that binds tightly to the negatively charged DNA, squeezing it into dense structures called chromatin.
However, new research shows that protamines also include other amino acids that vary by species and have special chemical changes after they are made. These changes, called post-translational modifications, alter how the proteins work.
This study, published in Nature Structural & Molecular Biology, reveals new roles for these lesser-known amino acids. Sy Redding, Ph.D., a co-author, explained, “We thought these proteins only had positive charges to bind DNA. But our work shows other amino acids also play important roles.”
Surprising Protein Modifications in Sperm
One puzzling finding was the presence of many chemical modifications on protamines, even though sperm cells do not actively produce new RNA or proteins.
Lindsay Moritz, Ph.D., co-first author, said, “These modifications must have a role in how DNA is packaged inside sperm.”
The researchers studied mice to test this. They focused on a modified lysine amino acid found in mouse protamines. When lysine was replaced by alanine—a similar amino acid that cannot be chemically modified—the sperm developed abnormal shapes. These sperm also led to problems in embryo development and reduced fertility.
Interestingly, replacing lysine with arginine, which also carries a positive charge, did not fix the problem. This means the role of these amino acids is more than just charge-based binding.
Implications for Male Infertility and IVF
Male infertility often has no clear cause, making this research especially important. Samantha Schon, M.D., co-first author, noted, “These protein modifications open a new path for understanding infertility. They might also help diagnose fertility issues and improve IVF outcomes by better understanding early embryo development.”
Next Steps in Understanding Sperm Formation
The team plans to study the detailed mechanisms of sperm DNA packaging further. Their goal is to recreate this process fully in the lab, which could lead to better fertility treatments in the future.
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