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Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
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Protein sequences encode safeguards against aggregation.

Joke Reumers1, Sebastian Maurer-Stroh, Joost Schymkowitz

  • 1Switch Laboratory, VIB, Vrije Universiteit Brussel, Brussels, Belgium.

Human Mutation
|January 22, 2009
PubMed
Summary
This summary is machine-generated.

Protein aggregation is inherent to protein structure, but natural selection favors sequences without it. This study reveals "gatekeeper residues" that prevent aggregation, and mutations disrupting them increase disease risk.

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Area of Science:

  • Biochemistry and Molecular Biology
  • Genetics
  • Structural Biology

Background:

  • Protein structure is constrained by functional requirements, leading to unavoidable protein aggregation.
  • Natural selection typically eliminates sequences prone to aggregation due to reduced fitness.
  • Aggregation-prone regions are often flanked by specific residues, termed 'gatekeepers'.

Purpose of the Study:

  • To analyze the distribution and variation of aggregation patterns in the human proteome.
  • To investigate the role of gatekeeper residues in preventing protein aggregation.
  • To determine if mutations disrupting gatekeeper motifs are associated with human diseases.

Main Methods:

  • Utilized the TANGO algorithm to analyze aggregation patterns in the human proteome.
  • Examined the enrichment of charged residues and proline as gatekeepers.
  • Analyzed disease-associated mutations from the UniProt database for disruptions in gatekeeper motifs.

Main Results:

  • Confirmed that gatekeeper residues (charged residues and proline) flank aggregation-prone regions.
  • Observed widespread redundancy in the usage of gatekeeper residues.
  • Found a significant enrichment of mutations disrupting gatekeeper motifs in disease-associated mutations.
  • Identified key proteins like p53 and huntingtin with extensively gatekept aggregating regions.

Conclusions:

  • Gatekeeper residues play a crucial role in preventing potentially harmful protein aggregation.
  • Mutations that remove or disrupt these gatekeeper residues can increase susceptibility to various diseases.
  • Disruption of gatekeeper motifs is implicated in disorders including van der Woude syndrome, X-linked Fabry disease, and limb-girdle muscular dystrophy.