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Structural basis of actin sequestration by thymosin-beta4: implications for WH2 proteins.

ABSTRACT: The WH2 (Wiscott-Aldridge syndrome protein homology domain 2) repeat is an actin interacting motif found in monomer sequestering and filament assembly proteins. We have stabilized the prototypical WH2 family member, thymosin-beta4 (Tbeta4), with respect to actin, by creating a hybrid between gelsolin domain 1 and the C-terminal half of Tbeta4 (G1-Tbeta4). This hybrid protein sequesters actin monomers, severs actin filaments and acts as a leaky barbed end cap. Here, we present the structure of the G1-Tbeta4:actin complex at 2 A resolution. The structure reveals that Tbeta4 sequesters by capping both ends of the actin monomer, and that exchange of actin between Tbeta4 and profilin is mediated by a minor overlap in binding sites. The structure implies that multiple WH2 motif-containing proteins will associate longitudinally with actin filaments. Finally, we discuss the role of the WH2 motif in arp2/3 activation.

SUBMITTER: Irobi E

PROVIDER: S-EPMC517612 | biostudies-literature | 2004 Sep

REPOSITORIES: biostudies-literature

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Structural basis of actin sequestration by thymosin-beta4: implications for WH2 proteins.

Irobi Edward E Aguda Adeleke H AH Larsson Mårten M Guerin Christophe C Yin Helen L HL Burtnick Leslie D LD Blanchoin Laurent L Robinson Robert C RC

The EMBO journal 20040826 18

The WH2 (Wiscott-Aldridge syndrome protein homology domain 2) repeat is an actin interacting motif found in monomer sequestering and filament assembly proteins. We have stabilized the prototypical WH2 family member, thymosin-beta4 (Tbeta4), with respect to actin, by creating a hybrid between gelsolin domain 1 and the C-terminal half of Tbeta4 (G1-Tbeta4). This hybrid protein sequesters actin monomers, severs actin filaments and acts as a leaky barbed end cap. Here, we present the structure of th ...[more]

PMID: 15329672

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Project description:AimTo investigate whether serum thymosin beta4 can provide diagnostic or prognostic information in liver failure patients caused by chronic hepatitis B virus (HBV) infection.MethodsSerum thymosin beta4 levels were measured in 30 patients with acute-on-chronic liver failure (ACLF), 31 patients with chronic liver failure (CLF), 30 patients with compensated liver cirrhosis (CR) and 32 patients with chronic hepatitis B and 30 healthy controls. Serum thymosin beta4 levels were measured by enzyme-linked immunosorbent assay and Child-Pugh and model for end-stage liver disease (MELD) scores were calculated for each patient on admission.ResultsCompared with healthy controls, serum thymosin beta4 levels in ACLF, CLF, CR and chronic hepatitis B patients were significantly lower, 6.5047 (4.7879-10.5314) microg/mL vs 0.4632 (0.2759-0.8768) microg/mL, 0.6981 (0.5209-1.2008) microg/mL, 1.8053 (0.8110-2.3397) microg/mL, 3.7803 (1.8570-6.4722) microg/mL, respectively (P < 0.001). The levels of thymosin beta4 in liver failure (ACLF or CLF) patients were markedly lower than that in CR (P < 0.001), and a difference was also found between CLF and ACLF patients (P = 0.038). In patients with chronic liver disease, there was a positive relationship between thymosin beta4 levels and albumin, choline esterase, and platelet (P < 0.001), and negative relationship with alanine aminotransferase (P = 0.020), aspartate aminotransferase, total bilirubin, international normalized ratio of prothrombin time, and Child-Pugh and MELD scores (P < 0.001). Of the 61 liver failure patients, the thymosin beta4 levels of non-survivors were significantly lower than that of survivors (P = 0.007). Receiver operating characteristics analysis identified a thymosin beta4 cutoff level of 0.5708 microg/mL for predicting poor prognosis in all liver failure patients. The serial thymosin beta4 values were observed in 13 liver failure inpatients. Lower initial values were observed in the death. While greater improvement in thymosin beta4 value was found in those who recovered from the disease.ConclusionSerum thymosin beta4 can be used as an important potential predictor for liver failure caused by chronic HBV infection.

Dataset Information

Structural basis of actin sequestration by thymosin-beta4: implications for WH2 proteins.

Publications

Structural basis of actin sequestration by thymosin-beta4: implications for WH2 proteins.

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