The Hidden Structural Grammar of Truncation in the Human Proteome

How does the human body alter protein structures to completely change their functions? While alternative splicing and truncation generate tens of thousands of protein variants, how these changes impact homodimers, the foundational units of cellular signaling, has remained largely unmapped.

In our latest study, Alper Karagöl and I conducted a proteome-wide analysis to uncover the hidden rules governing these transitions.

Leveraging the AlphaFold Database, we systematically analyzed 5,168 canonical-versus-truncated homodimer pairs across the human proteome. Rather than finding chaotic destruction, we discovered a universal structural grammar. While truncation leads to structural conservation in 56.4% of pairs, it causes complete interface ablation in 26.1% and partial destabilization in 17.5%. Strikingly, in 4.0% of cases, truncation actually triggers the emergence of an entirely new, high-confidence interface from a sub-threshold baseline.

Two predictable rules govern these architectural shifts. A topological asymmetry shows that N-terminal losses are 1.6-fold more likely to preserve protein interfaces. Meanwhile, a biophysical rule links the emergence of new interfaces to elevated levels of intrinsic protein disorder.

The full manuscript is available on bioRxiv: https://www.biorxiv.org/content/10.64898/2026.05.06.723091v1