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Structure and interaction of ubiquitin-associated domain of human Fas-associated factor 1

Jinsue Song1, Joon Kyu Park, Jae-Jin Lee

  • 1Magnetic Resonance Team, Korea Basic Science Institute, 804-1 Yangchung-Ri, Ochang, Chungbuk, Korea.

Protein Science : a Publication of the Protein Society
|September 2, 2009
PubMed

Insights

Fas-associated factor 1 (FAF1) has a ubiquitin-associated domain (hFAF1-UBA) that binds ubiquitin chains. This structural insight explains how FAF1 recognizes polyubiquitin, impacting its roles in disease.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Biochemistry

Background:

  • Fas-associated factor 1 (FAF1) is a multidomain protein involved in various biological processes, including cancer and neurodegenerative diseases.
  • FAF1 interacts with proteins in the Fas-signaling pathway, Hsp70, p97/VCP, and polyubiquitinated proteins.
  • The precise mechanisms of FAF1's function, particularly its interaction with ubiquitin, remain unclear.

Purpose of the Study:

  • To determine the crystal structure of the ubiquitin-associated domain of human FAF1 (hFAF1-UBA).
  • To investigate the interaction of hFAF1-UBA with ubiquitin and ubiquitin-like proteins using nuclear magnetic resonance (NMR).
  • To elucidate the structural basis of polyubiquitin recognition by FAF1.

Main Methods:

  • X-ray crystallography to determine the structure of hFAF1-UBA.
  • Nuclear magnetic resonance (NMR) spectroscopy to study protein-ligand interactions.
  • Biochemical assays to assess binding specificity.

Main Results:

  • The hFAF1-UBA domain adopts a canonical three-helical bundle structure.
  • hFAF1-UBA selectively binds to mono- and di-ubiquitin (Lys48-linked).
  • Binding to di-ubiquitin involves hydrophobic interactions and induces a conformational change in di-ubiquitin; no binding was observed for SUMO-1 or NEDD8.

Conclusions:

  • The study provides the first structural characterization of the hFAF1-UBA domain.
  • FAF1's ubiquitin-binding domain exhibits specificity for certain ubiquitin chain types.
  • These findings offer structural insights into how FAF1 recognizes polyubiquitin, potentially explaining its roles in disease pathways.

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