Beyond the Binding Site: The Role of the β2 – β3 Loop and Extra-Domain Structures in PDZ Domains

Mostarda, Stefano; Gfeller, David; Rao, Francesco

doi:10.1371/journal.pcbi.1002429

Cited by 43 publications

(57 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…25,26 In MAGI PDZ1 for example, an extended C-terminal loop makes direct interactions with Arg -4 , Arg -5 and Thr -6 of the peptide ligand and mutation in this C-terminal loop decreases the binding affinity drastically. 27 Thus, from previous work 11,12,14,24,27 together with the present data we conclude that some PDZ domains contain certain structural elements at their C-terminus, which have a direct effect on binding affinity. …”

Section: Discussionsupporting

confidence: 84%

Interactions outside the Boundaries of the Canonical Binding Groove of a PDZ Domain Influence Ligand Binding

et al. 2012

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 84%

Interactions outside the Boundaries of the Canonical Binding Groove of a PDZ Domain Influence Ligand Binding

et al. 2012

View full text Add to dashboard Cite

“…6C). The role of the interaction between β2-β3 loop and α3 helix has been already shown in an earlier study (51). Interestingly, there exists a significant population (6%) for the intrahelical i − i + 4 salt bridge formation between the side chains of E395-R399 in the unbound state (Fig.…”

Section: Population Shift Of Hydrogen-bonded Network Leads To Allostericsupporting

confidence: 68%

Hidden electrostatic basis of dynamic allostery in a PDZ domain

Kumawat

Chakrabarty

2017

Proc. Natl. Acad. Sci. U.S.A.

138

View full text Add to dashboard Cite

Allosteric effect implies ligand binding at one site leading to structural and/or dynamical changes at a distant site. PDZ domains are classic examples of dynamic allostery without conformational changes, where distal side-chain dynamics is modulated on ligand binding and the origin has been attributed to entropic effects. In this work, we unearth the energetic basis of the observed dynamic allostery in a PDZ3 domain protein using molecular dynamics simulations. We demonstrate that electrostatic interaction provides a highly sensitive yardstick to probe the allosteric modulation in contrast to the traditionally used structure-based parameters. There is a significant population shift in the hydrogen-bonded network and salt bridges involving side chains on ligand binding. The ligand creates a local energetic perturbation that propagates in the form of dominolike changes in interresidue interaction pattern. There are significant changes in the nature of specific interactions (nonpolar/ polar) between interresidue contacts and accompanied side-chain reorientations that drive the major redistribution of energy. Interestingly, this internal redistribution and rewiring of side-chain interactions led to large cancellations resulting in small change in the overall enthalpy of the protein, thus making it difficult to detect experimentally. In contrast to the prevailing focus on the entropic or dynamic effects, we show that the internal redistribution and population shift in specific electrostatic interactions drive the allosteric modulation in the PDZ3 domain protein.A llosteric regulation of proteins plays a key role in physiological cell functions, biochemical and signal transduction pathways, and drug discovery (1-3). It has remained a challenge to understand how the thermodynamic perturbation caused by ligand binding at one site would propagate and modulate the structure and dynamics of distal regions of proteins. The prevailing models of structure-based allostery (4, 5) do not apply to the more recent examples of allostery without conformational change such as PDZ domain (6), CAP dimer (7), and met repressor (8). These examples have triggered the concept of dynamic allostery, where the side-chain dynamics is modulated on ligand binding and the origin has often been attributed to changes in the conformational entropy (9, 10). The modern view of allostery invokes a thermodynamic picture, where a population shift among preexisting conformational states occurs on binding the allosteric effector (11-13). It has also been suggested in the context of allostery without conformational change that "not observed does not imply that it is not there" (10) because crystallographic techniques may not resolve the relatively minor population shifts. An interesting idea has emerged that all proteins might be allosteric in nature (14).PDZ domain has been a classic model system to study single domain allostery without major structural changes (9, 15, 16) (Fig. 1A). PDZ domains are evolutionary conserved proteinprotein interaction module...

show abstract

“…However, the strongest effects were observed for residues 329–334, which are located in the β2–β3 loop. Interactions between residues in this loop of PSD-95-PDZ3 and the side chain of Lys-4 in KKETAV have been proposed previously [33]. Furthermore, binding studies have revealed a determinant role of Lys-4 in the binding affinity of KKETAV, although this interaction was not observed in the crystal structure of the complex due to lack of resolution of the Lys-4 side chain [19].…”

Section: Resultsmentioning

confidence: 91%

Post-Translational Modifications Modulate Ligand Recognition by the Third PDZ Domain of the MAGUK Protein PSD-95

et al. 2014

View full text Add to dashboard Cite

The relative promiscuity of hub proteins such as postsynaptic density protein-95 (PSD-95) can be achieved by alternative splicing, allosteric regulation, and post-translational modifications, the latter of which is the most efficient method of accelerating cellular responses to environmental changes in vivo. Here, a mutational approach was used to determine the impact of phosphorylation and succinimidation post-translational modifications on the binding affinity of the postsynaptic density protein-95/discs large/zonula occludens-1 (PDZ3) domain of PSD-95. Molecular dynamics simulations revealed that the binding affinity of this domain is influenced by an interplay between salt-bridges linking the α3 helix, the β2–β3 loop and the positively charged Lys residues in its high-affinity hexapeptide ligand KKETAV. The α3 helix is an extra structural element that is not present in other PDZ domains, which links PDZ3 with the following SH3 domain in the PSD-95 protein. This regulatory mechanism was confirmed experimentally via thermodynamic and NMR chemical shift perturbation analyses, discarding intra-domain long-range effects. Taken together, the results presented here reveal the molecular basis of the regulatory role of the α3 extra-element and the effects of post-translational modifications of PDZ3 on its binding affinity, both energetically and dynamically.

show abstract

Beyond the Binding Site: The Role of the β2 – β3 Loop and Extra-Domain Structures in PDZ Domains

Cited by 43 publications

References 49 publications

Interactions outside the Boundaries of the Canonical Binding Groove of a PDZ Domain Influence Ligand Binding

Interactions outside the Boundaries of the Canonical Binding Groove of a PDZ Domain Influence Ligand Binding

Hidden electrostatic basis of dynamic allostery in a PDZ domain

Post-Translational Modifications Modulate Ligand Recognition by the Third PDZ Domain of the MAGUK Protein PSD-95

Contact Info

Product

Resources

About