Human recombinant [C22A] FK506‐binding protein amide hydrogen exchange rates from mass spectrometry match and extend those from NMR

Zhang, Zhongqi; Li, Weiqun; Logan, Timothy M.; Li, Ming; Marshall, Alan G.

doi:10.1002/pro.5560061015

Cited by 79 publications

(50 citation statements)

References 53 publications

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“…Data were analyzed by using an in-house analysis package. Time-courses of deuterium incorporation were generated after fitting the HDX data by using a maximum-entropy method (23).…”

Section: Hdx Fourier Transform Ion Cyclotron Resonance (Ft-icr) Mass mentioning

confidence: 99%

KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients

Gajiwala

Christensen

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Most gastrointestinal stromal tumors (GISTs) exhibit aberrant activation of the receptor tyrosine kinase (RTK) KIT. The efficacy of the inhibitors imatinib mesylate and sunitinib malate in GIST patients has been linked to their inhibition of these mutant KIT proteins. However, patients on imatinib can acquire secondary KIT mutations that render the protein insensitive to the inhibitor. Sunitinib has shown efficacy against certain imatinib-resistant mutants, although a subset that resides in the activation loop, including D816H/V, remains resistant. Biochemical and structural studies were undertaken to determine the molecular basis of sunitinib resistance. Our results show that sunitinib targets the autoinhibited conformation of WT KIT and that the D816H mutant undergoes a shift in conformational equilibrium toward the active state. These findings provide a structural and enzymologic explanation for the resistance profile observed with the KIT inhibitors. Prospectively, they have implications for understanding oncogenic kinase mutants and for circumventing drug resistance.kinase inhibitor ͉ signal transduction ͉ targeted therapy ͉ resistance mechanism ͉ cancer

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“…Data were analyzed by using an in-house analysis package. Time-courses of deuterium incorporation were generated after fitting the HDX data by using a maximum-entropy method (23).…”

Section: Hdx Fourier Transform Ion Cyclotron Resonance (Ft-icr) Mass mentioning

confidence: 99%

KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients

Gajiwala

Christensen

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

339

315

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“…Deuterium uptake profiles were fitted by a well characterized maximum entropy method algorithm (29). Although the maximum entropy method generally fits the experimental data well, it is limited to three rate constants and can deviate for very rapid exchange if the initial time points are not accurate due to incomplete mixing.…”

Section: Hdx and Liquid Chromatography (Lc)-electrospray Ionization mentioning

confidence: 99%

The N-terminal Domain of Escherichia coli Assimilatory NADPH-Sulfite Reductase Hemoprotein Is an Oligomerization Domain That Mediates Holoenzyme Assembly

Askenasy

Pennington

Tao

et al. 2015

Journal of Biological Chemistry

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Background: Assimilatory NADPH-sulfite reductase (SiR) is an essential metalloenzyme for sulfur metabolism made from two subunits. Results: We defined how the subunits of SiR assemble, with or without cofactors. Conclusion: One region of the metalloenzyme interacted either with its reductase partner when cofactors were formed or with itself when they were not. Significance: We propose a novel mechanism to regulate SiR assembly.

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“…Data were analyzed by an in-house analysis package (27). Time-course deuterium incorporation levels were generated by a maximum entropy method fitting method (28).…”

Section: Hdx Fourier Transform Ion Cyclotron Resonance Mass Spectromementioning

confidence: 99%

Uncovering of a Short Internal Peptide Activates a tRNA Synthetase Procytokine

Lee

Zhang

Marshall

et al. 2012

Journal of Biological Chemistry

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Background: Many tRNA synthetases have acquired expanded functions unrelated to their canonical aminoacylation function. Results: Structural analysis in solution showed that a subtle conformational change causes pinpointed exposure of an evolutionarily acquired ELR tripeptide of human tyrosyl-tRNA synthetase, which activates its cytokine function. Conclusion:The exposure of ELR of TyrRS confers cytokine activity. Significance: The TyrRS design facilitates functional expansion while retaining its essential role in translation.In higher organisms, aminoacyl-tRNA synthetases developed receptor-mediated ex-translational functions that are activated by various natural mechanisms. Hydrogen-deuterium exchange combined with mass spectrometry and small-angle x-ray scattering showed that activation of the cytokine function of the 528-amino acid human tyrosyl-tRNA synthetase was associated with pinpointed uncovering of a miniature internal ELR tripeptide that triggers receptor signaling. The results reveal the structural simplicity of how the ex-translational function is implemented.Aminoacyl-tRNA synthetases are ancient enzymes that catalyze the first step of protein synthesis by attaching amino acids onto their cognate tRNAs (1). In addition, in higher organisms, aminoacyl-tRNA synthetases gained a variety of expanded functions in cell signaling pathways ranging from vascular to inflammatory pathways, among others (2-6). These expansions, often implemented with secreted forms, developed in evolution through the incorporation of novel domains and sequence motifs that bear no impact on the protein synthesis function. That these additions were added at precise time points in evolution and are tightly regulated suggests that they played a role in the development of higher organisms (7-9).Human tyrosyl-tRNA synthetase (TyrRS) 2 is a 528-amino acid procytokine composed of two domains connected by a long linker that spans ϳ20 amino acids (Fig. 1A). The 364-amino acid N-terminal part (mini-TyrRS) is the catalytic aminoacylation domain and is active without the C-terminal domain (CTD) (10,11). At the evolutionary stage of insects, an ELR tripeptide was incorporated into the mini-TyrRS domain and has been retained in higher organisms. The ELR motif is the recognition element within CXC chemokines such as interleukin-8, which mediates the innate immune response as well as angiogenesis (12,13). Simultaneously, the CTD, which is a structural and functional homolog of human endothelial monocyte-activating polypeptide II (EMAP II), was appended to TyrRS. Previous work established that mini-TyrRS and the CTD have distinct cytokine activities associated with hematological and inflammatory pathways, whereas full-length TyrRS is inactive as a cytokine (14,15). Thus, the novel activities are observed only when the two domains of secreted TyrRS are separated by natural proteolysis at the interdomain linker.The crystal structures of mini-TyrRS and the CTD have separately been determined (16,17). In the mini-TyrRS domain, the ELR motif is mask...

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Human recombinant [C22A] FK506‐binding protein amide hydrogen exchange rates from mass spectrometry match and extend those from NMR

Cited by 79 publications

References 53 publications

KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients

KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients

The N-terminal Domain of Escherichia coli Assimilatory NADPH-Sulfite Reductase Hemoprotein Is an Oligomerization Domain That Mediates Holoenzyme Assembly

Uncovering of a Short Internal Peptide Activates a tRNA Synthetase Procytokine

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