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Related Concept Videos

Alternative RNA Splicing02:18

Alternative RNA Splicing

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Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
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Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
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In eukaryotic cells, nascent mRNA transcripts need to undergo many post-transcriptional modifications to reach the cell cytoplasm and translate into functional proteins. For a long time, transcription and pre-mRNA processing were considered two independent events that occur sequentially in the cell. However, it has now been well established that transcription and pre-mRNA processing are two simultaneous processes that are precisely regulated inside the cell.
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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

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Predicting the structural impact of human alternative splicing.

Yuxuan Song1, Chengxin Zhang1, Gilbert S Omenn1

  • 1Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.

Genome Biology
|September 17, 2025
PubMed
Summary

Alternative splicing significantly alters protein structures and functions, impacting post-translational modification sites. This study predicts structures for over 11,000 human isoforms, revealing cell-type specific expression patterns.

Keywords:
AlphaFold2Alternative splicingIsoform functionProtein structureSingle-Cell RNA-seq

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Area of Science:

  • Computational Biology
  • Structural Biology
  • Genomics

Background:

  • Neural networks advance protein structure prediction, but often neglect splice variants.
  • Alternative splicing generates diverse protein isoforms from a single gene, affecting protein structure and function.
  • Investigating structural implications of alternative splicing is crucial for understanding cellular complexity.

Purpose of the Study:

  • To predict structures for over 11,000 human protein isoforms using AlphaFold2.
  • To identify and characterize structural alterations induced by alternative splicing.
  • To link protein isoform structures to cell-type specific expression.

Main Methods:

  • Utilized AlphaFold2 for predicting structures of >11,000 human isoforms.
  • Applied multiple metrics (template matching, secondary structure, surface charge, radius of gyration, PTM site accessibility) to detect splicing-induced changes.
  • Integrated structure-based function prediction and single-cell RNA-seq data (Tabula Sapiens).

Main Results:

  • Identified splicing-induced changes in protein structure, surface charge, radius of gyration, and PTM site accessibility.
  • Observed instances of low structural similarity between isoforms despite high sequence identity.
  • Functional predictions revealed numerous differences between isoforms, often with a predominant loss of function compared to the reference.
  • Mapped isoform expression to specific cell types using single-cell RNA-seq data.

Conclusions:

  • This study provides a valuable resource for understanding the structure and function of splice isoforms.
  • Highlights the significant impact of alternative splicing on protein structure and cellular function.
  • Enables exploration of isoform structure and function across diverse human cell types.