A conserved fertilization complex bridges sperm and egg in vertebrates

From a quick skim: what's interesting about this study from an HN perspective is that they used Alphafold (or more specifically Alphafold-Multimer: https://www.biorxiv.org/content/10.1101/2021.10.04.463034v2....) to screen more than 1400 different proteins that were likely to be present on zebrafish sperm to see which ones might bind to other known sperm fertility factors.

Lo, and behold, they found a protein (i.e, the product of a particular zebrafish gene) that Alphafold-Multimer predicted would bind to two of the known sperm factors. And it turned out to be a kind of missing link: the three sperm proteins together were predicted form a stable structure. And, that structure ("complex") sticks to the only egg protein known to be required for fertilization! (Where all of this was first predicted using Alphafold-Multimer, then experimentally confirmed to some degree.)

Not only that, it turns out human versions ("orthologs") of these three sperm proteins exist, and their experimental evidence at least suggests that they stick together, forming a complex as well. Which presumably sticks to some human egg protein. Pretty neat.

Why this matters: Consider. 20 years ago, I briefly worked for a lab that used genetics to study fertilization in C. elegans (fast breeding, millimeter-long worms with a lot of infrastructure in place for scientific study). Sure, we were studying worms, but the PI had a personal interest in (in)fertility, and it was his long bet that fundamental research would help medicine solve infertility.

Now it looks like the bet is showing promise of paying off: back then, there didn't seem to be any vertebrate equivalents of the worm genes we found. Maybe worm fertilization was just too far removed. But the top "related article" is from my old lab (https://www.cell.com/current-biology/fulltext/S0960-9822(23)...) and the abstract points out that several worm genes they and related labs found are, in fact, equivalents of the vertebrate genes discussed in TFA! So progress accelerates.

Next step, design a drug to block it, and we have a new contraceptive that doesn't involve throwing a spanner in the works of anyone's endocrine system.

The animation illustrating the AlphaFold-predicted structural models of the trimeric sperm complex in zebrafish, mice and humans shows shocking similarity.

I remember Richard Dawkins talking about the "male fertility crisis" some years ago, and how little we still truly knew about it. Maybe this can shed some light.

I’ve never stumbled so much through a title….