PDZ Domain Binding Selectivity Is Optimized Across the Mouse Proteome

Stiffler, Michael A; Chen, Jiunn R; Grantcharova, Viara; Lei, Ying; Fuchs, D. Beate; Allen, John E.; Zaslavskaia, Lioudmila A.; MacBeath, Gavin

doi:10.1126/science.1144592

Cited by 337 publications

(594 citation statements)

References 24 publications

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“…It is therefore likely that extended PDZ domains are more prevalent than we expect. Consistent with our analysis, recent systematic PDZ domain/target interaction analysis revealed that over 30% of PDZ domains could not be obtained in bacterial overexpression systems (Stiffler et al, 2007;Wu et al, 2007;Tonikian et al, 2008). Based on our own experience in working with a large number of PDZ domains in the past decade, it is important to evaluate the boundaries of PDZ domains with great care as many PDZ domains require extended sequences for proper folding.…”

Section: Resultssupporting

confidence: 85%

“…With an expanded target ligand binding pocket, the PDZ binds to a region of the target that has a length longer than the canonical four amino acid residues. Other PDZ domains have been shown to bind atypically long target sequences (Stiffler et al, 2007;Tonikian et al, 2008). It will be interesting to investigate whether extensions contribute to the target binding specificity for other PDZ domains.…”

Section: Expansion Of the Target Ligand Binding Pocketmentioning

confidence: 99%

“…It is surprising and worth noting that the first structure of a PDZ domain (the third PDZ of PSD95) contained an additional Cterminal helix (Doyle et al, 1996); however, the functional importance of the extension was initially overlooked because it was spatially distal from the binding pocket. Although the 'classical' binding mode dictates that PDZ domains bind to the four most C-terminal residues of a particular target, there are cases where PDZ domains can bind to internal peptide regions or segments longer than four residues (Stiffler et al, 2007;Tonikian et al, 2008). The region of the target that interacts with PDZ is more commonly referred to as the PDZ binding motif (PBM).…”

Section: Introductionmentioning

confidence: 99%

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Extensions of PDZ domains as important structural and functional elements

et al. 2010

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ABSTRACT'Divide and conquer' has been the guiding strategy for the study of protein structure and function. Proteins are divided into domains with each domain having a canonical structural definition depending on its type. In this review, we push forward with the interesting observation that many domains have regions outside of their canonical definition that affect their structure and function; we call these regions 'extensions'. We focus on the highly abundant PDZ (PSD-95, DLG1 and ZO-1) domain. Using bioinformatics, we find that many PDZ domains have potential extensions and we developed an openly-accessible website to display our results (http:// bcz102.ust.hk/pdzex/). We propose, using well-studied PDZ domains as illustrative examples, that the roles of PDZ extensions can be classified into at least four categories: 1) protein dynamics-based modulation of target binding affinity, 2) provision of binding sites for macro-molecular assembly, 3) structural integration of multi-domain modules, and 4) expansion of the target ligand-binding pocket. Our review highlights the potential structural and functional importance of domain extensions, highlighting the significance of looking beyond the canonical boundaries of protein domains in general.

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Section: Resultssupporting

confidence: 85%

Section: Expansion Of the Target Ligand Binding Pocketmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Extensions of PDZ domains as important structural and functional elements

et al. 2010

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“…32 At one stage, PDZ domains were classified into two classes (type I and type II), but a more recent study concluded that binding specificity is more widely distributed across a sample of 157 mouse PDZ domains. 33 Moreover, it has been discussed that PDZ domain/peptide analyses may have oversimplified the understanding of these interactions in vivo, because two-site interactions that are likely a critical determinant of physiological PDZ binding are often overlooked. 34 Indeed, multimerization of PDZ-containing proteins and their receptor targets might constitute physiological regulatory mechanisms, and so the enhancement of avidity by multiple interactions of inherently weak ligands may be a common theme in BIRs and PDZs.…”

Section: Discussionmentioning

confidence: 99%

The mechanism of peptide-binding specificity of IAP BIR domains

et al. 2008

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We describe the peptide-binding specificity of the baculoviral IAP repeat (BIR) domains of the human inhibitor of apoptosis (IAP) proteins, X-linked IAP, cellular IAP1 and neuronal apoptosis inhibitory protein (NAIP). Synthetic peptide libraries were used to profile each domain, and we distinguish two types of binding specificity, which we refer to as type II and type III BIR domains. Both types have a dominant selectivity for Ala in the first position of the four N-terminal residues of the peptide ligands, which constitute a core recognition motif. Our analysis allows us to define the signature of type III BIRs that demonstrate a preference for Pro in the third residue of the ligand, resembling the classic IAP-binding motif (IBM). The signature of the type II BIRs was similar to type III, but with a striking absence of specificity for Pro in the third position, suggesting that the definition of an IBM must be modified depending on the type of BIR in question. These findings explain how subtle changes in the peptide-binding groove of IAP BIR domains can significantly alter the target protein selectivity. Our analysis allows for prediction of BIR domain protein-binding preferences, provides a context for understanding the mechanism of peptide selection and heightens our knowledge of the specificity of IAP antagonists that are being developed as cancer therapeutics. Cell Death and Differentiation (2008) 15, 920-928; doi:10.1038/cdd.2008 ; published online 1 February 2008Apoptosis is a highly regulated cellular signaling pathway that results in the elimination of unwanted cells from multicellular animals. The apoptotic signaling cascades can be initiated by various extracellular (extrinsic pathway) or intracellular (intrinsic pathway) stimuli and ultimately converge on the activation of a family of proteases known as the caspasesreviewed in Fuentes-Prior and Salvesen. 1 Once active, caspases cleave a limited number of substrates that results in the destruction of the cell and its eventual disposal by phagocytic cells.Members of the inhibitor of apoptosis (IAP) protein family have the unique ability to attenuate apoptosis induced through both intrinsic and extrinsic stimuli. It is well established that the X-linked IAP (XIAP) is capable of blocking apoptosis by direct inhibition of caspase-3, -7, and -9 -reviewed in Salvesen and Duckett 2 and Eckelman et al. 3 The means by which the other members of the IAP family inhibit apoptosis is less understood. Many IAPs have the capacity to bind caspases, yet lack the ability to directly inhibit the proteolytic activity of these enzymes -reviewed in Eckelman et al. 3 The defining feature of the IAP family is the presence of 1-3 baculoviral IAP repeat (BIR) domains. BIRs are small, B70-residue zinc-coordinated domains that have been identified as the regions essential to the IAP-caspase interaction. The BIR domain(s) are necessary for the antiapoptotic activity of most IAPs. Often a surface groove on the BIR domain endows it with an affinity toward extreme N-terminal epitopes...

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“…By clustering the binding induced fluctuation profiles of a diverse set of PDZ domains, we showed that ENM predicted normal modes not only can identify the structural regions and types of correlated fluctuations critical for binding of Class I and Class II peptides but also predicts binding selectivity of PDZs. 49 The challenge of PDZ domain (i.e., the reasons behind their selectivity and promiscuity) and their link to many different diseases has led to a number of important experimental 50,51 and computational 49,[52][53][54][55][56][57][58] studies. Niv and Weinstein also developed a flexible docking scheme (called PDZDocScheme), 56 which is based on simulated annealing molecular dynamics with the soft core potential or flexible binding site side chains, followed by rotamer optimization.…”

Section: Introductionmentioning

confidence: 99%

A flexible docking scheme to explore the binding selectivity of PDZ domains

Gerek

Ozkan

2010

Protein Science

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Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using ROSETTALIGAND, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 Å . We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately.

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PDZ Domain Binding Selectivity Is Optimized Across the Mouse Proteome

Cited by 337 publications

References 24 publications

Extensions of PDZ domains as important structural and functional elements

Extensions of PDZ domains as important structural and functional elements

The mechanism of peptide-binding specificity of IAP BIR domains

A flexible docking scheme to explore the binding selectivity of PDZ domains

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