An engineered heterodimeric model to investigate SULT1B1 dependence on intersubunit communication

Self-preservation is a typical property of living organisms, observed in the simplest prokaryotic cell as well as in the more complex pluricellular organisms. Surprisingly we found a self-preservation mechanism operating at the level of a single enzyme. Human glutathione transferase P1-1 operates in such a way towards either killer compounds (competitive and irreversible inhibitors) or physical factors (temperature and UV-rays), which could suppress its detoxicating and anti-cancer activity in the cell. This property, here termed ‘co-operative self-preservation’, is based on a structural intersubunit communication, by which one subunit, as a consequence of an inactivating modification, triggers a defence arrangement in the other subunit. Paradoxically this ability, developed during evolution for the survival of the cell, may not always be advantageous for us. In fact, glutathione transferase P1-1 is overexpressed in most tumour cells and pharmacological attempts to inhibit this enzyme in vivo, to prevent the drug resistance phenomenon during chemotherapy, may be thwarted by such self-preservation.

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Role for SUR2A ED Domain in Allosteric Coupling within the KATP Channel Complex

The Journal of General Physiology ◽

10.1085/jgp.200709852 ◽

2008 ◽

Vol 131 (3) ◽

pp. 185-196 ◽

Cited By ~ 14

Author(s):

Amy B. Karger ◽

Sungjo Park ◽

Santiago Reyes ◽

Martin Bienengraeber ◽

Roy B. Dyer ◽

...

Keyword(s):

Katp Channel ◽

Katp Channels ◽

Cooperative Interaction ◽

Amino Acid Residues ◽

Structural Adaptation ◽

Allosteric Coupling ◽

Binding Domains ◽

Allosteric Pathway ◽

Intersubunit Communication

Allosteric regulation of heteromultimeric ATP-sensitive potassium (KATP) channels is unique among protein systems as it implies transmission of ligand-induced structural adaptation at the regulatory SUR subunit, a member of ATP-binding cassette ABCC family, to the distinct pore-forming K+ (Kir6.x) channel module. Cooperative interaction between nucleotide binding domains (NBDs) of SUR is a prerequisite for KATP channel gating, yet pathways of allosteric intersubunit communication remain uncertain. Here, we analyzed the role of the ED domain, a stretch of 15 negatively charged aspartate/glutamate amino acid residues (948–962) of the SUR2A isoform, in the regulation of cardiac KATP channels. Disruption of the ED domain impeded cooperative NBDs interaction and interrupted the regulation of KATP channel complexes by MgADP, potassium channel openers, and sulfonylurea drugs. Thus, the ED domain is a structural component of the allosteric pathway within the KATP channel complex integrating transduction of diverse nucleotide-dependent states in the regulatory SUR subunit to the open/closed states of the K+-conducting channel pore.

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Intersubunit Communication in Hybrid Hexamers of K89L/A163G/S380A and C320S Mutants of Glutamate Dehydrogenase fromClostridium symbiosum†

Biochemistry ◽

10.1021/bi971419d ◽

1997 ◽

Vol 36 (48) ◽

pp. 15000-15005 ◽

Cited By ~ 3

Author(s):

Arun Goyal ◽

Suren Aghajanian ◽

Bronagh M. Hayden ◽

Xing-Guo Wang ◽

Paul C. Engel

Keyword(s):

Glutamate Dehydrogenase ◽

Intersubunit Communication

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Congenital myasthenia–related AChR δ subunit mutation interferes with intersubunit communication essential for channel gating

Journal of Clinical Investigation ◽

10.1172/jci34527 ◽

2008 ◽

Vol 118 (5) ◽

pp. 1867-1876 ◽

Cited By ~ 41

Author(s):

Xin-Ming Shen ◽

Taku Fukuda ◽

Kinji Ohno ◽

Steven M. Sine ◽

Andrew G. Engel

Keyword(s):

Channel Gating ◽

Congenital Myasthenia ◽

Intersubunit Communication

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Interaction of Residues Aspartate 549 and Arginine 404 Modulates Active Site Accessibility and Intersubunit Communication in the E1 Subunit of Escherichia coli Pyruvate Dehydrogenase Multienzyme Complex

The FASEB Journal ◽

10.1096/fasebj.21.5.a645-a ◽

2007 ◽

Vol 21 (5) ◽

Author(s):

Sachin Kale ◽

Frank Jordan

Keyword(s):

Escherichia Coli ◽

Pyruvate Dehydrogenase ◽

Active Site ◽

Multienzyme Complex ◽

Intersubunit Communication

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Probing allosteric interactions in homo-oligomeric molecular machines using solution NMR spectroscopy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2116325118 ◽

2021 ◽

Vol 118 (50) ◽

pp. e2116325118

Author(s):

Yuki Toyama ◽

Lewis E. Kay

Keyword(s):

Nmr Spectroscopy ◽

Structural Dynamics ◽

Experimental Studies ◽

Molecular Machines ◽

Solution Nmr ◽

Allosteric Interactions ◽

Allosteric Communication ◽

Weight Protein ◽

Solution Nmr Spectroscopy ◽

Intersubunit Communication

Developments in solution NMR spectroscopy have significantly impacted the biological questions that can now be addressed by this methodology. By means of illustration, we present here a perspective focusing on studies of a number of molecular machines that are critical for cellular homeostasis. The role of NMR in elucidating the structural dynamics of these important molecules is emphasized, focusing specifically on intersubunit allosteric communication in homo-oligomers. In many biophysical studies of oligomers, allostery is inferred by showing that models specifically including intersubunit communication best fit the data of interest. Ideally, however, experimental studies focusing on one subunit of a multisubunit system would be performed as an important complement to the more traditional bulk measurements in which signals from all components are measured simultaneously. Using an approach whereby asymmetric molecules are prepared in concert with NMR experiments focusing on the structural dynamics of individual protomers, we present examples of how intersubunit allostery can be directly observed in high-molecular-weight protein systems. These examples highlight some of the unique roles of solution NMR spectroscopy in studies of complex biomolecules and emphasize the important synergy between NMR and other atomic resolution biophysical methods.

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