Multivalent Binding of Formin-binding Protein 21 (FBP21)-Tandem-WW Domains Fosters Protein Recognition in the Pre-spliceosome

Klippel, Stefan; Wieczorek, Marek; Schümann, Michael; Krause, Eberhard; Marg, Berenice; Seidel, Thorsten; Meyer, Tim; Knapp, Ernst‐Walter; Freund, Christian

doi:10.1074/jbc.m111.265710

Cited by 27 publications

(49 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, recent NMR studies suggest that the WW1–WW2 tandem module of YAP2 binds with higher affinity to peptide ligands containing a tandem copy of PPXY motifs compared with monovalent ligands . Similar observations have also been documented for the WW tandem domains of FBP21 pre‐mRNA splicing factor . While we acknowledge the shortcomings of our present work, it is clear that the binding of WW domains of YAP2 to monovalent ligands is governed by negative cooperativity.…”

Section: Discussionsupporting

confidence: 76%

Ligand binding to WW tandem domains of YAP2 transcriptional regulator is under negative cooperativity

et al. 2014

View full text Add to dashboard Cite

YAP2 transcriptional regulator drives a multitude of cellular processes, including the newly discovered Hippo tumor suppressor pathway, by virtue of the ability of its WW domains to bind and recruit PPXY-containing ligands to specific subcellular compartments. Herein, we employ an array of biophysical tools to investigate allosteric communication between the WW tandem domains of YAP2. Our data show that the WW tandem domains of YAP2 negatively cooperate when binding to their cognate ligands. Moreover, the molecular origin of such negative cooperativity lies in an unfavorable entropic contribution to the overall free energy relative to ligand binding to isolated WW domains. Consistent with this notion, the WW tandem domains adopt a fixed spatial orientation such that the WW1 domain curves outwards and stacks onto the binding groove of WW2 domain, thereby sterically hindering ligand binding to both itself and its tandem partner. Although ligand binding to both WW domains disrupts such interdomain stacking interaction, they reorient themselves and adopt an alternative fixed spatial orientation in the liganded state by virtue of their ability to engage laterally so as to allow their binding grooves to point outwards and away from each other. In short, while the ability of WW tandem domains to aid ligand binding is well-documented, our demonstration that they may also be subject to negative binding cooperativity represents a paradigm shift in our understanding of the molecular action of this ubiquitous family of protein modules.

show abstract

Section: Discussionsupporting

confidence: 76%

Ligand binding to WW tandem domains of YAP2 transcriptional regulator is under negative cooperativity

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The relatively weak affinity of a single PRM found in the Sm tails argues that avidity effects due to the presence of multiple motifs play an important role for high affinity binding by increasing the local concentration of PRM motifs available for OCRE binding. We note that avidity effects provided by multiple binding sites have also been observed for other PRM binding domains (Varani et al, 2000; Klippel et al, 2011), and that this feature is reminiscent of the recognition of dimethyl-arginine residues in the Sm tails by Tudor domains (Tripsianes et al, 2011). On the other hand, the weak binding affinity of a single motif indicates that the interaction between RBM5 and SmN/B/B’ may have been selected to be transient, as expected for a regulatory interaction that needs to promote interactions with the spliceosome but also needs to be disrupted at later steps of the splicing reaction.…”

Section: Discussionsupporting

confidence: 56%

“…Interestingly, a somewhat related PRM motif in the CD2 protein (PPPPGHR) was reported to interact with the GYF domain of the CD2BP2 protein (Freund et al, 2002). The CD2BP2 GYF domain and the FBP21 WW domain have been previously implicated in binding to the PRM sequences of SmB, suggesting that interactions between PRMs and these factors may be critical for the function of these proteins in spliceosome regulation (Bedford et al, 1998; Klippel et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

Structural basis for the recognition of spliceosomal SmN/B/B’ proteins by the RBM5 OCRE domain in splicing regulation

Mourão

Bonnal

Soni

et al. 2016

eLife

View full text Add to dashboard Cite

The multi-domain splicing factor RBM5 regulates the balance between antagonistic isoforms of the apoptosis-control genes FAS/CD95, Caspase-2 and AID. An OCRE (OCtamer REpeat of aromatic residues) domain found in RBM5 is important for alternative splicing regulation and mediates interactions with components of the U4/U6.U5 tri-snRNP. We show that the RBM5 OCRE domain adopts a unique β–sheet fold. NMR and biochemical experiments demonstrate that the OCRE domain directly binds to the proline-rich C-terminal tail of the essential snRNP core proteins SmN/B/B’. The NMR structure of an OCRE-SmN peptide complex reveals a specific recognition of poly-proline helical motifs in SmN/B/B’. Mutation of conserved aromatic residues impairs binding to the Sm proteins in vitro and compromises RBM5-mediated alternative splicing regulation of FAS/CD95. Thus, RBM5 OCRE represents a poly-proline recognition domain that mediates critical interactions with the C-terminal tail of the spliceosomal SmN/B/B’ proteins in FAS/CD95 alternative splicing regulation.

show abstract

“…The presence of these processes may explain the differences in the measured apparent affinity of WW domains toward the α‐hENaC peptide , which may have functional significance. Moreover, while the present work examines binding of monovalent ligands studies have shown that several tandem WW domains function in a cooperative manner when binding multivalent ligands , including tandem WW domains that undergo conformational rearrangements to recognize target multivalent ligands , and this structural versatility of multi‐WW domains to interact independently or as organized systems has contributed to their success in nature. However, the possible effect of such synergistic mechanisms to tandem WW domain dynamics has not been examined in detail and represents a future study.…”

Section: Discussionmentioning

confidence: 95%

Multiple WW domains of Nedd4‐1 undergo conformational exchange that is quenched upon peptide binding

et al. 2017

View full text Add to dashboard Cite

The third WW domain (WW3*) of the ubiquitin ligase human neuronal precursor cell expressed developmentally downregulated gene 4-1 (hNedd4-1) was reported to bind its PY motif peptide by a coupled folding-binding equilibrium. However, it is unknown whether these thermodynamic properties are retained in the context of neighboring hNedd4-1 domains. In this report, NMR data show that the WW3* displays a fold-unfold equilibrium in the presence of neighboring WW domains, and that similar fold-unfold equilibria also likely exist for neighboring WW domains. These equilibria are quenched upon interaction with peptide. Thus, the binding mechanism of hNedd4-1 WW domains to proteins involves coupled folding and binding equilibria, and this mechanism may be a general feature that modulates peptide affinities of WW domains.

show abstract

Multivalent Binding of Formin-binding Protein 21 (FBP21)-Tandem-WW Domains Fosters Protein Recognition in the Pre-spliceosome

Cited by 27 publications

References 41 publications

Ligand binding to WW tandem domains of YAP2 transcriptional regulator is under negative cooperativity

Ligand binding to WW tandem domains of YAP2 transcriptional regulator is under negative cooperativity

Structural basis for the recognition of spliceosomal SmN/B/B’ proteins by the RBM5 OCRE domain in splicing regulation

Multiple WW domains of Nedd4‐1 undergo conformational exchange that is quenched upon peptide binding

Contact Info

Product

Resources

About