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Client recruitment mechanism of the cytosolic Fe-S cluster assembly targeting complex

Wenjie Ren1, Yuxin Huang1, Min Hu1

  • 1Greater Bay Biomedical InnoCenter, Shenzhen Bay Laboratory, Shenzhen, 518132, China.

The EMBO Journal
|January 4, 2026
PubMed

Insights

Researchers discovered a hidden pentapeptide motif that helps cytosolic Fe-S cluster assembly targeting complex (CTC) recognize essential Fe-S proteins. This finding clarifies how these proteins acquire vital cofactors for cellular functions like DNA repair.

Area of Science:

  • Biochemistry and Molecular Biology
  • Cellular Biology
  • Genetics and Genomics

Background:

  • Eukaryotic Fe-S proteins are crucial for fundamental biological processes.
  • These proteins require Fe-S cofactors, typically acquired via the cytosolic Fe-S cluster assembly targeting complex (CTC).
  • The specific recognition mechanisms between CTC and its client Fe-S proteins are not well understood.

Purpose of the Study:

  • To identify the molecular determinants governing CTC's recognition of its client Fe-S proteins.
  • To elucidate the mechanism by which Fe-S proteins acquire their essential cofactors.
  • To understand how this recognition impacts cellular functions, particularly genome maintenance.

Main Methods:

  • Identification of a consensus pentapeptide motif in human Fe-S proteins.
  • Analysis of the motif's role in CTC-client engagement and iron incorporation.
  • Structure-guided affinity-purification mass spectrometry (AP-MS) to investigate the CTC interactome.

Main Results:

  • A hidden consensus pentapeptide motif was identified as a key recognition signature for CTC.
  • This motif is particularly prevalent in DNA/RNA processing enzymes involved in genome maintenance.
  • Defects in the motif impair CTC recognition, iron incorporation, and client enzymatic activities, affecting DNA repair.
  • A conserved surface pocket on CTC recognizes both the pentapeptide motif and a previously known C-tail motif.
  • AP-MS revealed the pocket-dependent human CTC interactome, potentially identifying novel Fe-S proteins.

Conclusions:

  • The study deciphers a sequence signature-directed mechanism for CTC client recruitment.
  • This mechanism is critical for the acquisition of Fe-S cofactors by essential cellular proteins.
  • The findings provide a foundation for identifying additional Fe-S proteins and understanding their roles in cellular functions.
Keywords:
CTCCluster AcquisitionDNA RepairFe-S ProteinsPentapeptide Motif

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