The acidic tail of HMGB1 regulates its secondary structure and conformational flexibility: A circular dichroism and molecular dynamics simulation study

Anggayasti, Wresti L.; Ogino, Kenta; Yamamoto, Eiji; Helmerhorst, Erik; Yasuoka, Kenji; Mancera, Ricardo L.

doi:10.1016/j.csbj.2020.05.012

Cited by 10 publications

(3 citation statements)

References 47 publications

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“…The tail is normally formed by an Asp/Glu-repeat element, which is highly conserved among HMGB1 orthologues. This repeat element stabilizes HMGB1’s secondary structure and is crucial for its DNA-bending capacity (Belgrano et al 2013 ; Anggayasti et al 2020 ). The variant is not only absent from the databases but also no variant listed in gnomAD contains an amino acid residue except Glu or Asp in the acidic tail domain.…”

Section: Resultsmentioning

confidence: 99%

Genome sequencing in families with congenital limb malformations

et al. 2021

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The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.

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Section: Resultsmentioning

confidence: 99%

Genome sequencing in families with congenital limb malformations

et al. 2021

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“…HMGB1 is a damage‐associated molecular pattern (DAMP) molecule that triggers the progression of hepatic steatosis by inducing signals upon interaction with RAGE (Anggayasti et al, 2020). We found that HMGB1 expression was also increased in the livers of the old mice, suggesting the aberrant activation of the HMGB1/ RAGE signaling in the livers of the old mice.…”

Section: Discussionmentioning

confidence: 99%

Aging‐induced aberrant RAGE/PPARα axis promotes hepatic steatosis via dysfunctional mitochondrial β oxidation

Wan

Chen

et al. 2020

Aging Cell

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“…For each system of ALK, MD simulations were performed in explicit water environment, generating multiple μs-length trajectories (i.e., 15 replicas of 1 μs for each system) and yielding an accumulated sampling of 60 μs. These simulating multiple and independent μs-length trajectories were required to achieve solid statistics for the analysis of different dynamics of ALK, because multiple ns-to-μs MD trajectories are essential to reveal the interdependent dynamics of protein domains and their interactions with the inhibitors ( Anggayasti et al, 2020 ; Jang et al, 2020 ; Liang, et la., 2020 ; Navarro et al, 2020 ; Shevchenko et al, 2020 ; Shibata et al, 2020 ; Li et al, 2020b ).…”

Section: Results and Discssionmentioning

confidence: 99%

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Liang

Wang

et al. 2021

Front. Cell Dev. Biol.

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Anaplastic lymphoma kinase (ALK) is validated as a therapeutic molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the feasibility of targeted therapies exerted by ALK inhibitors is inevitably hindered owing to drug resistance. The emergence of clinically acquired drug mutations has become a major challenge to targeted therapies and personalized medicines. Thus, elucidating the mechanism of resistance to ALK inhibitors is helpful for providing new therapeutic strategies for the design of next-generation drug. Here, we used molecular docking and multiple molecular dynamics simulations combined with correlated and energetical analyses to explore the mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant ALK I1171N/F1174I. We found that the conformational dynamics of the ALK kinase domain was reduced by the double mutations I1171N/F1174I. Moreover, energetical and structural analyses implied that the double mutations largely disturbed the conserved hydrogen bonding interactions from the hinge residues Glu1197 and Met1199 in the lorlatinib-bound state, whereas they had no discernible adverse impact on the binding affinity and stability of gilteritinib-bound state. These discrepancies created the capacity of the double mutant ALK I1171N/F1174I to confer drug resistance to lorlatinib. Our result anticipates to provide a mechanistic insight into the mechanism of drug resistance induced by ALK I1171N/F1174I that are resistant to lorlatinib treatment in NSCLC.

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The acidic tail of HMGB1 regulates its secondary structure and conformational flexibility: A circular dichroism and molecular dynamics simulation study

Cited by 10 publications

References 47 publications

Genome sequencing in families with congenital limb malformations

Genome sequencing in families with congenital limb malformations

Aging‐induced aberrant RAGE/PPARα axis promotes hepatic steatosis via dysfunctional mitochondrial β oxidation

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

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