Allosteric Control of O2 Reactivity in Rieske Oxygenases

AbstractLegionella pneumophila infects eukaryotic cells by forming a replicative organelle – the Legionella containing vacuole. During this process, the bacterial protein DrrA/SidM is secreted and manipulates the activity and post-translational modification (PTM) states of the vesicular trafficking regulator Rab1. As a result, Rab1 is modified with an adenosine monophosphate (AMP), and this process is referred to as AMPylation. Here, we use a chemical approach to stabilise low-affinity Rab:DrrA complexes in a site-specific manner to gain insight into the molecular basis of the interaction between the Rab protein and the AMPylation domain of DrrA. The crystal structure of the Rab:DrrA complex reveals a previously unknown non-conventional Rab-binding site (NC-RBS). Biochemical characterisation demonstrates allosteric stimulation of the AMPylation activity of DrrA via Rab binding to the NC-RBS. We speculate that allosteric control of DrrA could in principle prevent random and potentially cytotoxic AMPylation in the host, thereby perhaps ensuring efficient infection by Legionella.

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Conformational equilibria in allosteric control of Hsp70 chaperones

Molecular Cell ◽

10.1016/j.molcel.2021.07.039 ◽

2021 ◽

Vol 81 (19) ◽

pp. 3919-3933.e7

Author(s):

Wei Wang ◽

Qinglian Liu ◽

Qun Liu ◽

Wayne A. Hendrickson

Keyword(s):

Allosteric Control ◽

Conformational Equilibria

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Conformational changes involving ammonia tunnel formation and allosteric control in GMP synthetase

Archives of Biochemistry and Biophysics ◽

10.1016/j.abb.2014.01.004 ◽

2014 ◽

Vol 545 ◽

pp. 22-32 ◽

Cited By ~ 9

Author(s):

Justin C. Oliver ◽

Ravidra Gudihal ◽

John W. Burgner ◽

Anthony M. Pedley ◽

Alexander T. Zwierko ◽

...

Keyword(s):

Conformational Changes ◽

Allosteric Control ◽

Ammonia Tunnel ◽

Gmp Synthetase

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Engineering an Allosteric Control of Protein Function

The Journal of Physical Chemistry B ◽

10.1021/acs.jpcb.0c11640 ◽

2021 ◽

Vol 125 (7) ◽

pp. 1806-1814

Author(s):

Yashavantha L. Vishweshwaraiah ◽

Jiaxing Chen ◽

Nikolay V. Dokholyan

Keyword(s):

Protein Function ◽

Allosteric Control

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DNA-Induced Allosteric Control Regulates Activation of Cas12A

Biophysical Journal ◽

10.1016/j.bpj.2020.11.369 ◽

2021 ◽

Vol 120 (3) ◽

pp. 17a

Author(s):

Pablo R. Arantes ◽

Aakash Saha ◽

Martin Jinek ◽

Giulia Palermo

Keyword(s):

Allosteric Control

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Targeting Allosteric Control Mechanisms in Heat Shock Protein 70 (Hsp70)

Current Topics in Medicinal Chemistry ◽

10.2174/1568026616666160413140911 ◽

2016 ◽

Vol 16 (25) ◽

pp. 2729-2740 ◽

Cited By ~ 30

Author(s):

Xiaokai Li ◽

Hao Shao ◽

Isabelle R. Taylor ◽

Jason E. Gestwicki

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Heat Shock Protein 70 ◽

Control Mechanisms ◽

Allosteric Control

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Towards comprehensive allosteric control over protein activity

10.1101/384198 ◽

2018 ◽

Author(s):

Enrico Guarnera ◽

Igor N. Berezovsky

Keyword(s):

Ligand Binding ◽

Molecular Mechanisms ◽

Allosteric Regulation ◽

Mode Switching ◽

Contact Network ◽

Protein Activity ◽

Theoretical Understanding ◽

Functional Sites ◽

Allosteric Control ◽

Allosteric Communication

AbstractOn the basis of the perturbation nature of allosteric communication, a computational framework is proposed for estimating the energetics of signaling caused by the ligand binding and mutations. The perturbations are modelled as alterations of the strenght of interactions in the protein contact network in the binding sites and neighborhoods of mutated residues. The combination of protein harmonic modelling with effect of perturbations and the estimate of local partition functions allow one to evaluate the energetics of allosteric communication at single residue level. The potential allosteric effect of a protein residue position, modulation range, is given by the difference between responses to stabilizing and destabilizing mutations. We show a versatility of the approach on three case studies of proteins with different mechanisms of allosteric regulation, testing it on their known regulatory and functional sites. Allosteric Signaling Maps (ASMs) obtained on the basis of residue-by-residue scanning are proposed as a comprehensive tool to explore a relationship between mutations allosterically modulating protein activity and those that mainly affect protein stability. Analysis of ASMs shows distance dependence of the mode switching in allosteric signaling, emphasizing the role of domains/subunits in protein allosteric communication as elements of a percolative system. Finally, ASMs can be used to complement and tune already existing signaling and to design new elements of allosteric regulation.SignificanceUniversality of allosteric signaling in proteins, molecular machines, and receptors and great advantages of prospected allosteric drugs in highly specific, non-competitive, and modulatory nature of their actions call for deeper theoretical understanding of allosteric communication. In the energy landscape paradigm underliying the molecular mechanisms of protein function, allosteric signalling is the result of any perturbation, such as ligand binding, mutations, intermolecular interactions etc. We present a computational model, allowing to tackle the problem of modulating the energetics of protein allosteric communication. Using this method, Allosteric Signaling Maps (ASMs) are proposed as an approach to exhaustively describe allosteric signaling in the protein, making it possible to take protein activity under allosteric control.

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