Comparative Structural and Energetic Analysis of WW Domain–Peptide Interactions

Schleinkofer, Karin; Wiedemann, Urs Achim; Otte, Livia; Wang, Ting; Krause, Gerd; Oschkinat, Hartmut; Wade, Rebecca C.

doi:10.1016/j.jmb.2004.09.063

Cited by 38 publications

(32 citation statements)

References 59 publications

(87 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5c). There is evidence, as well, that interaction with this class of WW domains is enhanced by acidic peptide residues or phosphorylation (33,35,36). Interactions with regions N-and C-terminal to the PY motif could also inhibit binding.…”

Section: Discussionmentioning

confidence: 99%

An Expanded WW Domain Recognition Motif Revealed by the Interaction between Smad7 and the E3 Ubiquitin Ligase Smurf2

Chong

Lin

Wrana

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Smurf2 is an E3 ubiquitin ligase that drives degradation of the transforming growth factor-␤ receptors and other targets. Recognition of the receptors by Smurf2 is accomplished through an intermediary protein, Smad7. Here we have demonstrated that the WW3 domain of Smurf2 can directly bind to the Smad7 polyproline-tyrosine (PY) motif. Of particular interest, the highly conserved WW domain binding site Trp, which interacts with target PY motifs, is a Phe in the Smurf2 WW3 domain. To examine this interaction, the solution structure of the complex between the Smad7 PY motif region (ELESPPPPYSRYPMD) and the Smurf2 WW3 domain was determined. The structure reveals that, in addition to binding the PY motif, the WW3 domain binds six residues C-terminal to the PY motif (PY-tail). Although the Phe in the WW3 domain binding site decreases affinity relative to the canonical Trp, this is balanced by additional interactions between the PY-tail and the ␤1-strand and ␤1-␤2 loop of the WW3 domain. The interaction between the Smurf2 WW3 domain and the Smad7 PY motif is the first example of PY motif recognition by a WW domain with a Phe substituted for the binding site Trp. This unusual interaction allows the Smurf2 WW3 domain to recognize a subset of PY motif-containing proteins utilizing an expanded surface to provide specificity.Transforming growth factor-␤ (TGF-␤) 4 and bone morphogenic protein (BMP) pathways play key roles in many biological processes including tumor suppression and embryonic development (1). Signals from these extracellular ligands are transduced through transmembrane Ser/Thr kinases that phosphorylate intracellular transcription factors known as the receptor-regulated Smad (R-Smad) proteins (2). In addition to R-Smads (Smads 1-3, 5 and 8), the Smad family includes the common mediator Smad (Smad4) and inhibitory Smads (I-Smads: Smads 6 and 7). Control of these pathways is exerted to some degree by ubiquitin-mediated targeted degradation of Smad proteins and receptors, in part involving the Smad ubiquitination regulatory factor (Smurf) proteins (3, 4). Smurf1 and Smurf2 are HECT-type E3 ubiquitin ligases that ubiquitinate specific proteins, marking them for degradation by the proteasome (5). The Smad proteins can themselves be ubiquitinated by Smurf proteins. For example, Smurf1 efficiently targets BMP-responsive Smad1 and Smad5 for degradation (3). Smurf2 has been implicated in ubiquitination of Smad1 and Smad2 (6, 7). In addition, the Smad proteins can function as adapters to enhance Smurf-dependent ubiquitination of other target proteins (4,8,9). For example, Smad7, which binds to the TGF-␤ receptors and Smurfs, acts as an adapter allowing Smurf1 and Smurf2 to bind to and ubiquitinate the TGF-␤ receptors, targeting them for degradation (4, 9).Recent reports suggest that the Smurf homologues Itch, Nedd4-2, and WWP1 also function in regulating TGF-␤ signaling pathways. Itch can both ubiquitinate Smad2 and enhance Smad2 phosphorylation in mouse embryonic fibroblasts (10). Nedd4-2 and WWP1 both bind to Smads 2...

show abstract

Section: Discussionmentioning

confidence: 99%

An Expanded WW Domain Recognition Motif Revealed by the Interaction between Smad7 and the E3 Ubiquitin Ligase Smurf2

Chong

Lin

Wrana

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…However, as the study of unfolded proteins has expanded, it has become increasingly well recognized that their low sequence specificity is important in a large number of low affinity protein-protein interactions in signal transduction, protein transcription, and other pathways (Sudol, 1998;Macias et al, 2002;Musacchio, 2002;Hicks and Hsu, 2004;Polverini et al, 2008;Zhao et al, 2010). Common domains such as WW (named for a conserved Trp-Trp; Schleinkofer et al, 2004), GYF (conserved Gly-Tyr-Phe; Gu et al, 2005), and Src homology 3 (SH3) can bind and respond to a broad range of Pro-rich sequences. They do so through shallow hydrophobic sites but the molecular details of the interaction and thermodynamic measurements demonstrate the overwhelming importance of H-bonding.…”

Section: Interaction Of Pro-rich Pp-ii Sequences With Globular Domainsmentioning

confidence: 99%

Invited review: Caseins and the casein micelle: Their biological functions, structures, and behavior in foods

Holt

Carver

Ecroyd

et al. 2013

Journal of Dairy Science

385

240

View full text Add to dashboard Cite

A typical casein micelle contains thousands of casein molecules, most of which form thermodynamically stable complexes with nanoclusters of amorphous calcium phosphate. Like many other unfolded proteins, caseins have an actual or potential tendency to assemble into toxic amyloid fibrils, particularly at the high concentrations found in milk. Fibrils do not form in milk because an alternative aggregation pathway is followed that results in formation of the casein micelle. As a result of forming micelles, nutritious milk can be secreted and stored without causing either pathological calcification or amyloidosis of the mother's mammary tissue. The ability to sequester nanoclusters of amorphous calcium phosphate in a stable complex is not unique to caseins. It has been demonstrated using a number of noncasein secreted phosphoproteins and may be of general physiological importance in preventing calcification of other biofluids and soft tissues. Thus, competent noncasein phosphoproteins have similar patterns of phosphorylation and the same type of flexible, unfolded conformation as caseins. The ability to suppress amyloid fibril formation by forming an alternative amorphous aggregate is also not unique to caseins and underlies the action of molecular chaperones such as the small heat-shock proteins. The open structure of the protein matrix of casein micelles is fragile and easily perturbed by changes in its environment. Perturbations can cause the polypeptide chains to segregate into regions of greater and lesser density. As a result, the reliable determination of the native structure of casein micelles continues to be extremely challenging. The biological functions of caseins, such as their chaperone activity, are determined by their composition and flexible conformation and by how the casein polypeptide chains interact with each other. These same properties determine how caseins behave in the manufacture of many dairy products and how they can be used as functional ingredients in other foods. aBStraCtA typical casein micelle contains thousands of casein molecules, most of which form thermodynamically stable complexes with nanoclusters of amorphous calcium phosphate. Like many other unfolded proteins, caseins have an actual or potential tendency to assemble into toxic amyloid fibrils, particularly at the high concentrations found in milk. Fibrils do not form in milk because an alternative aggregation pathway is followed that results in formation of the casein micelle. As a result of forming micelles, nutritious milk can be secreted and stored without causing either pathological calcification or amyloidosis of the mother's mammary tissue. The ability to sequester nanoclusters of amorphous calcium phosphate in a stable complex is not unique to caseins. It has been demonstrated using a number of noncasein secreted phosphoproteins and may be of general physiological importance in preventing calcification of other biofluids and soft tissues. Thus, competent noncasein phosphoproteins have similar patterns of phosp...

show abstract

“…51 One of this indices called the electrostatic potential has been shown to correlated to biological function of biopolymers. 52,53 In the present study, we selected as example QSAR study of the RNAs of the family of 1-aminocyclopropane-1-carboxylic acid (ACC) oxidases known as ACO. This plant enzyme participates in ethylene production from S-adenosylmethionine via ACC, the immediate precursor of ethylene.…”

Section: Introductionmentioning

confidence: 99%

2D‐RNA‐coupling numbers: A new computational chemistry approach to link secondary structure topology with biological function

et al. 2007

View full text Add to dashboard Cite

Methods for prediction of proteins, DNA, or RNA function and mapping it onto sequence often rely on bioinformatics alignment approach instead of chemical structure. Consequently, it is interesting to develop computational chemistry approaches based on molecular descriptors. In this sense, many researchers used sequence-coupling numbers and our group extended them to 2D proteins representations. However, no coupling numbers have been reported for 2D-RNA topology graphs, which are highly branched and contain useful information. Here, we use a computational chemistry scheme: (a) transforming sequences into RNA secondary structures, (b) defining and calculating new 2D-RNA-coupling numbers, (c) seek a structure-function model, and (d) map biological function onto the folded RNA. We studied as example 1-aminocyclopropane-1-carboxylic acid (ACC) oxidases known as ACO, which control fruit ripening having importance for biotechnology industry. First, we calculated tau(k)(2D-RNA) values to a set of 90-folded RNAs, including 28 transcripts of ACO and control sequences. Afterwards, we compared the classification performance of 10 different classifiers implemented in the software WEKA. In particular, the logistic equation ACO = 23.8 . tau(1)(2D-RNA) + 41.4 predicts ACOs with 98.9%, 98.0%, and 97.8% of accuracy in training, leave-one-out and 10-fold cross-validation, respectively. Afterwards, with this equation we predict ACO function to a sequence isolated in this work from Coffea arabica (GenBank accession DQ218452). The tau(1)(2D-RNA) also favorably compare with other descriptors. This equation allows us to map the codification of ACO activity on different mRNA topology features. The present computational-chemistry approach is general and could be extended to connect RNA secondary structure topology to other functions.

show abstract

Comparative Structural and Energetic Analysis of WW Domain–Peptide Interactions

Cited by 38 publications

References 59 publications

An Expanded WW Domain Recognition Motif Revealed by the Interaction between Smad7 and the E3 Ubiquitin Ligase Smurf2

An Expanded WW Domain Recognition Motif Revealed by the Interaction between Smad7 and the E3 Ubiquitin Ligase Smurf2

Invited review: Caseins and the casein micelle: Their biological functions, structures, and behavior in foods

2D‐RNA‐coupling numbers: A new computational chemistry approach to link secondary structure topology with biological function

Contact Info

Product

Resources

About