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Intrinsic bias of the genetic code shapes the folding and stability landscapes of microproteins

Yabo Guo1, Ti Qin2, Jiancheng Luo3

  • 1Department of Biochemistry, Department of Cardiology of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.

Molecular Cell
|May 20, 2026
PubMed

Insights

Most human microproteins are unstable and rapidly degraded due to their genetic code. High GC content in microprotein genes leads to intrinsically disordered peptides targeted for proteasomal degradation.

Area of Science:

  • Molecular Biology
  • Genetics
  • Immunology

Background:

  • Thousands of non-canonical open reading frames (ORFs) in the human transcriptome are translated into microproteins.
  • Many microproteins have ribosome occupancy comparable to canonical proteins.
  • Most microproteins do not accumulate as stable proteins but are presented by human leukocyte antigen class I (HLA-I) molecules, suggesting immunomodulatory roles.

Purpose of the Study:

  • To explore the folding and stability landscape of microproteins.
  • To reveal a fundamental rule connecting the genetic code, protein folding, and stability.
  • To understand the mechanisms underlying microprotein instability and degradation.

Main Methods:

  • Structural modeling of microproteins.
  • Parallel profiling of microprotein stability.
  • Analysis of microprotein-coding sequences and their GC content.
  • Investigating the role of Cullin-RING E3 ubiquitin ligase (CRL)-dependent proteasomal degradation.

Main Results:

  • Most microproteins are intrinsically disordered and rapidly degraded.
  • High GC content in microprotein-coding sequences enriches for specific residues (glycine, arginine, alanine, proline).
  • These residues promote structural disorder and degradation via terminal-residue motif-mediated CRL-dependent proteasomal pathways.
  • A quantitative rule linking high GC content to constrained protein evolvability was established.

Conclusions:

  • High GC content in microprotein genes dictates their intrinsic disorder and rapid degradation.
  • This mechanism explains differential targeting of microproteins versus canonical proteins by surveillance machinery.
  • The findings provide insights into how genetic code constraints influence protein stability and evolvability.
Keywords:
GC contentgenetic codelncORFmicroproteinnon-canonical translationprotein stabilityprotein structureuORF

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