Structural basis for controlling the dimerization and stability of the WW domains of an atypical subfamily

Ohnishi, Satoshi; Tochio, N.; Tomizawa, T.; Akasaka, Ryogo; Harada, T.; Seki, Eiko; Sato, Manami; Watanabe, Satoru; Fujikura, Yukiko; Koshiba, S.; Terada, Takaho; Shirouzu, Mikako; Tanaka, Akiko; Kigawa, T.; Yokoyama, Shigeyuki

doi:10.1110/ps.035329.108

Cited by 9 publications

(11 citation statements)

References 27 publications

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“…The expressions of these TLRs were slightly elevated in the presence of cholesterol and/or inflammation regardless of treatment modality or liver pathology. This result is consistent with the results of a previous study showing that the in vivo responses of both hepatocytes and Kupffer cells to TLR-2 and TLR-4 ligands are very weak [35] . Regarding other inflammatory genes, the mRNA expressions of IL-β, TNF-α, and MCP-1 in the liver did not differ significantly among the 4 experimental groups, except for MCP-1 in group II.…”

Section: Discussionsupporting

confidence: 93%

Cholesterol-Induced Non-Alcoholic Fatty Liver Disease and Atherosclerosis Aggravated by Systemic Inflammation

Kim

Seo

et al. 2014

PLoS ONE

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Although triglyceride accumulation in the liver causes non-alcoholic fatty liver disease (NAFLD), hypercholesterolemia is also a main cause of NAFLD as well as atherosclerosis. However, NAFLD and atherosclerosis have not been investigated simultaneously in animal models fed a high-cholesterol diet. Moreover, it is unclear whether systemic inflammation can exacerbate both pathologies in the same model. Accordingly, this study investigated the effect of additional systemic inflammation on NAFLD and atherosclerosis induced by cholesterol overload in wild animals. New Zealand white rabbits were divided into 4 groups: groups I (control) and II received normal chow, and groups III and IV received a 1% cholesterol diet. To induce inflammation via toll-like receptor (TLR)-4 signaling, groups II and IV received subcutaneous injections of 0.5 mL of 1% carrageenan every 3 weeks. After 3 months, total cholesterol markedly increased in groups III and IV, and the serum expressions of systemic inflammatory markers were elevated in the groups II–IV. Early NAFLD lesions (e.g., mild fatty changes in the liver with sporadic fibrosis) and atherosclerosis (e.g., intimal hyperplasia composed of foam cells) were observed in both the liver and aorta specimens from group III, and advanced lesions were observed in group IV. The expressions of inflammatory cellular receptors, TLR-2 and TLR-4, in the aorta gradually increased from group I to IV but were similar in the liver in groups II–IV. Cholesteryl ester (CE) levels were higher in group IV than in group III, although the difference was not significant. CE levels in the aorta were similar between groups III and IV. Systemic inflammation can simultaneously exacerbate existing early lesions due to cholesterol overload in both the liver and aorta of rabbits. However, the cellular response of inflammatory receptors and expression of cholesterol metabolites differ between these organs.

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Section: Discussionsupporting

confidence: 93%

Cholesterol-Induced Non-Alcoholic Fatty Liver Disease and Atherosclerosis Aggravated by Systemic Inflammation

Kim

Seo

et al. 2014

PLoS ONE

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“…Understanding the folding behavior of the WW domain in solution may be essential to unravel the molecular causes of the GIH syndrome 11 38 . The WW domain from PQBP1 appears to have an unstable and disordered fold, at variance with most other WW domain structures determined so far in solution 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 . Although uncommon, conformational exchange between open and closed forms have been reported for other WW domains 19 21 32 .…”

Section: Discussioncontrasting

confidence: 62%

“…The solution NMR structures of several WW domains have been determined revealing a common fold but also different degrees of conformational stability. While in general the domain is remarkably well ordered 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 , in some cases it presents conformational exchange 19 21 32 . The structure has been also studied in the presence of a binding peptide which might stabilize the fold 17 19 28 30 31 32 .…”

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confidence: 99%

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Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome

Pucheta-Martinez

D’Amelio

Lelli

et al. 2016

Sci Rep

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WW domains are small domains present in many human proteins with a wide array of functions and acting through the recognition of proline-rich sequences. The WW domain belonging to polyglutamine tract-binding protein 1 (PQBP1) is of particular interest due to its direct involvement in several X chromosome-linked intellectual disabilities, including Golabi-Ito-Hall (GIH) syndrome, where a single point mutation (Y65C) correlates with the development of the disease. The mutant cannot bind to its natural ligand WBP11, which regulates mRNA processing. In this work we use high-field high-resolution NMR and enhanced sampling molecular dynamics simulations to gain insight into the molecular causes the disease. We find that the wild type protein is partially unfolded exchanging among multiple beta-strand-like conformations in solution. The Y65C mutation further destabilizes the residual fold and primes the protein for the formation of a disulphide bridge, which could be at the origin of the loss of function.

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“…In contrast, the WW domains of WWOX adopt a front-to-back mode of association, wherein the concave palm of one hand (WW1) latches onto the convex back (WW2) of the other. Interestingly, while WW2 domains of both WWOX and SAV1 share rather high sequence similarity with the WW2 domain of MAGI1, the latter predominantly adopts a monomeric conformation in solution (47), thereby implying that sequence similarity alone is a poor predictor of the ability of WW domains to dimerize. Importantly, the ability of WW domains of WWOX to physically associate and attain a fixed spatial orientation also appears to somewhat resemble the tandem WW domains of Prp40 yeast splicing factor (38).…”

Section: Ligand Binding To Ww1 Domain Is Coupled To the Dissociation mentioning

confidence: 99%

Structural insights into the functional versatility of WW domain-containing oxidoreductase tumor suppressor

Farooq

2015

Exp Biol Med (Maywood)

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Recent work on WWOX tumor suppressor is beginning to shed new light on both the molecular mechanism of action of its WW domains as well as the contiguous catalytic domain. Herein, the structural basis underlying the ability of WW1 domain to bind to various physiological ligands and how the orphan WW2 tandem partner synergizes its ligand binding in the context of WW1-WW2 tandem module of WWOX is discussed. Notably, the WW domains within the WW1-WW2 tandem module physically associate so as to adopt a fixed spatial orientation relative to each other. In this manner, the association of WW2 domain with WW1 hinders ligand binding to the latter. Consequently, ligand binding to WW1 domain not only results in the displacement of WW2 lid but also disrupts the fixed orientation of WW domains in the liganded conformation. Equally importantly, structure-guided functional approach suggests that the catalytic domain of WWOX likely serves as a retinal oxidoreductase that catalyzes the reversible oxidation and reduction of all-trans-retinal. Collectively, this review provides structural insights into the functional versatility of a key signaling protein with important implications on its biology.

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Structural basis for controlling the dimerization and stability of the WW domains of an atypical subfamily

Cited by 9 publications

References 27 publications

Cholesterol-Induced Non-Alcoholic Fatty Liver Disease and Atherosclerosis Aggravated by Systemic Inflammation

Cholesterol-Induced Non-Alcoholic Fatty Liver Disease and Atherosclerosis Aggravated by Systemic Inflammation

Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome

Structural insights into the functional versatility of WW domain-containing oxidoreductase tumor suppressor

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