Abstract
FBP11/HYPA is a mammalian homologue of yeast splicing factor Prp40. The first WW domain of FBP11/HYPA (FBP11 WW1) is essential for preventing severe neurological diseases such as Huntington disease and Rett syndrome and strongly resembles the WW domain of FCA, the essential regulator for flowering time control. We have solved the structure of FBP11 WW1 and a Pro-Pro-Leu-Pro ligand complex, and demonstrated the binding mechanism with mutational analysis using surface plasmon resonance. The overall structure of FBP11 WW1 in the complex form is quite similar to the structures of WW domains from Group I and IV in complexes. In addition, conformation of FBP11 WW1 does not change much upon ligand binding. The binding orientation of the ligand against FBP11 WW1 is the same as that of the Group IV WW domain-ligand complex, but opposite to that of the Group I complex. The ligand interacts with two grooves formed by surface aromatic residues. The Pro and Leu residues in the ligand interact with the grooves and the Loop I region of FBP11 WW1, respectively, which are necessary interactions for binding the ligand. Interestingly, the two aromatic grooves recognize the Pro residues in entirely different manners, which allows FBP11 WW1 to recognize shorter sequences than the SH3 domain. Combined with homology models of other WW domains, the present report shows the detailed mechanism of ligand binding by Group II/III WW domains, and provides information useful in designing drugs to treat neurodegenerative diseases.
Highlights
FBP112/HYPA is a mammalian homologue of yeast splicing factor Prp40 and acts to enhance the efficiency of splicing in mammalian cells [1]
The first WW domain of FBP11/ HYPA is highly similar to the FCA WW domain (FCA WW), which binds to a PL motif of FY in Arabidopsis thaliana [6]
Based on structure model analyses, Sudol, Macias [11, 13, 14], and we have proposed that Group II/III WW domains have a common surface patch referred to as “the second -Xaa-Probinding groove (XP2 groove)” that is composed of a few aromatic residues on the surface of Group II/III WW domains
Summary
FBP112/HYPA is a mammalian homologue of yeast splicing factor Prp and acts to enhance the efficiency of splicing in mammalian cells [1]. FBP11/HYPA has two WW domains that bind to prolinerich ligands, including those with the -Pro-Pro-Leu-Prosequence, the PL motif [5]. The first WW domain of FBP11/ HYPA is highly similar to the FCA WW domain (FCA WW), which binds to a PL motif of FY in Arabidopsis thaliana [6]. Recent structural studies have revealed that WW domains have a -Xaa-Pro- binding groove (XP groove) that recognizes proline residues [7, 8]. Several studies have shown that many Group II and III WW domains have common ligand specificity, leading to the new definition of one larger group referred to as Group II/III, which was formed by merging Groups II and III (10 –12). The XP2 groove has a composition similar to the XP groove that recognizes the -Xaa-Pro- sequence in ligands of all WW domains including Groups I and IV as well as Group II/III and is expected to contribute to the recognition of Pro-rich sequences in ligands for Group II/III WW domains
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