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Computational Prediction of Amino Acid Preferences of Potentially Multispecific Peptide-Binding Domains Involved in Protein-Protein Interactions
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Structural basis for polyproline recognition by the FE65 WW domain

Muthuraman Meiyappan1, Gabriel Birrane1, John A A Ladias1

  • 1Molecular Medicine Laboratory and Macromolecular Crystallography Unit, Division of Experimental Medicine, Harvard Institutes of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Journal of Molecular Biology
|August 10, 2007
PubMed

Insights

The FE65 WW domain binds Mena peptides via polyproline recognition, crucial for brain development and APP signaling. Structural analysis reveals an induced-fit mechanism for this interaction, offering therapeutic design insights.

Area of Science:

  • Neuroscience
  • Structural Biology
  • Biochemistry

Background:

  • The FE65 protein is vital for brain development and amyloid precursor protein (APP) signaling.
  • FE65 interacts with the mammalian enabled (Mena) protein via its WW domain, recognizing polyproline sequences essential for neuronal development.

Purpose of the Study:

  • To determine the crystal structures of the human FE65 WW domain bound to Mena peptides.
  • To elucidate the molecular mechanisms of polyproline ligand recognition by the FE65 WW domain.

Main Methods:

  • X-ray crystallography was used to obtain structures of the FE65 WW domain (residues 253-289) in apo and liganded forms.
  • The liganded forms involved peptides PPPPPPLPP and PPPPPPPPPL, corresponding to Mena residues.

Main Results:

  • The FE65 WW domain possesses two ligand-binding grooves (XP and XP2) that accommodate Mena peptides in a polyproline helical II conformation.
  • Ligand binding occurs through the PPPPP motif in a forward orientation, involving an induced-fit mechanism for the XP2 groove.
  • The binding mode resembles polyproline interactions with SH3 domains.

Conclusions:

  • The study elucidates the molecular basis for FE65 WW domain's polyproline ligand selection.
  • These findings provide a structural framework for designing molecules to modulate FE65 WW-ligand interactions, impacting neuronal development and APP signaling.

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