Hierarchical binding of cofactors to the AAA ATPase p97.
The hexameric AAA ATPase p97 is involved in several human proteinopathies and mediates ubiquitin-dependent protein degradation among other essential cellular processes. Via its N-terminal domain (N domain), p97 interacts with multiple regulatory cofactors including the UFD1/NPL4 heterodimer and members of the "ubiquitin regulatory X" (UBX) domain protein family; however, the ... principles governing cofactor selectivity remain to be deciphered. Our crystal structure of the FAS-associated factor 1 (FAF1)UBX domain in complex with the p97N domain reveals that the signature Phe-Pro-Arg motif known to be crucial for interactions of UBX domains with p97 adopts a cis-proline configuration, in contrast to a cis-trans mixture we derive for the isolated FAF1UBX domain. Biochemical studies confirm that binding critically depends on a proline at this position. Furthermore, we observe that the UBX proteins FAF1 and UBXD7 only bind to p97-UFD1/NPL4, but not free p97, thus demonstrating for the first time a hierarchy in p97-cofactor interactions.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Adenosine Triphosphatases, Amino Acid Motifs, Amino Acid Sequence, Calorimetry, Carrier Proteins, Chromatography, Gel, Coenzymes, Conserved Sequence, Crystallography, X-Ray, Humans, Molecular Sequence Data, Nuclear Proteins, Protein Binding, Protein Interaction Domains and Motifs, Protein Structure, Quaternary, Protein Structure, Tertiary, Proteins, Surface Properties, Titrimetry, Ubiquitin, Ubiquitinated Proteins
Adaptor Proteins, Signal Transducing, Adenosine Triphosphatases, Amino Acid Motifs, Amino Acid Sequence, Calorimetry, Carrier Proteins, Chromatography, Gel, Coenzymes, Conserved Sequence, Crystallography, X-Ray, Humans, Molecular Sequence Data, Nuclear Proteins, Protein Binding, Protein Interaction Domains and Motifs, Protein Structure, Quaternary, Protein Structure, Tertiary, Proteins, Surface Properties, Titrimetry, Ubiquitin, Ubiquitinated Proteins
Structure
Date: Jun. 08, 2011
PubMed ID: 21645854
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