Systematic Assessment of Protein C-Termini Mutated in Human Disorders

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Proteins possess a carboxyl terminus (C-terminus) containing critical binding and trafficking sequence determinants.
• These determinants, known as minimotifs or short linear motifs, can be affected by post-translational modifications (PTMs).
• Previous work identified eight C-terminal mutations causing human diseases, highlighting the significance of these regions.

Purpose of the Study:

• To investigate the frequency of disease-causing mutations within C-terminal minimotifs.
• To identify novel molecular mechanisms underlying genetic disorders associated with C-terminal protein alterations.
• To specifically analyze the impact of mutations affecting post-translational modifications (PTMs) in C-terminal minimotifs.

Main Methods:

• Data mining of ClinVar for disease variants.
• Analysis of Minimotif Miner and the C-terminome databases for PTMs.
• Cross-referencing with RefSeq protein sequences to identify potential disease-causing variants in C-terminal minimotifs.

Main Results:

• Identified 20 potential disease-causing variants in C-terminal minimotifs.
• Confirmed six variants with previously reported PTM disruption mechanisms.
• Generated new hypotheses for nine variants involving mutated C-terminal minimotifs and PTMs, affecting diverse genes and diseases.

Conclusions:

• Mutated minimotifs in protein C-termini are an infrequent but significant cause of human genetic diseases.
• The study provides new molecular insights into nine disease variants, emphasizing the role of PTMs.
• The analytical approach can be expanded to discover more disease mechanisms as databases grow.