Distinct Allosteric Networks Underlie Mechanistic Speciation of ABC Transporters

Acar, Burcin; Rose, Jessica; Fas, Burcu Aykac; Ben‐Tal, Nir; Lewinson, Oded; Haliloğlu, Türkan

doi:10.1016/j.str.2020.03.014

Cited by 25 publications

(39 citation statements)

References 71 publications

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“…These results strongly supported the idea that maltose‐bound MalE stimulates the ATPase activity of the transporter by promoting MalK closure [12]. Consistent with this, a recent allosteric study suggested that MalE controls the conformational changes in MalEFGK 2 such that the dynamics of the MalE‐docking sites precedes, and that of the ATP sites follow [9]. Finally, EPR spectroscopy suggested that MalK was semi‐open in the ADP‐bound post‐translocation state [12,35,36].…”

Section: Crystal Structures Of Malefgk2: Shaping the View Of The Transupporting

confidence: 75%

Structures of ABC transporters: handle with care

2020

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In the past two decades, the ATP-binding cassette (ABC) transporters' field has undergone a structural revolution. The importance of structural biology to the development of the field of ABC transporters cannot be overstated, as the ensemble of structures not only revealed the architecture of ABC transporters but also shaped our mechanistic view of these remarkable molecular machines. Nevertheless, we advocate that the mechanistic interpretation of the structures is not trivial and should be carried out with prudence. Herein, we bring several examples of structures of ABC transporters that merit re-interpretation via careful comparison to experimental data. We propose that it is of the upmost importance to place new structures within the context of the available experimental data.

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Section: Crystal Structures Of Malefgk2: Shaping the View Of The Transupporting

confidence: 75%

Structures of ABC transporters: handle with care

2020

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“…Clearly, the existence of a pathway is a necessary but not sufficient condition for causality. The study of the effect of suppression or delay of the motion of one region on the motion of the other, [49] and/or the analysis of the energetics of allosteric signaling [50][51][52] have been recently proposed to address causality of the correlation.…”

Section: Discussionmentioning

confidence: 99%

Mechanical coupling in the nitrogenase complex

et al. 2021

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The enzyme nitrogenase reduces dinitrogen to ammonia utilizing electrons, protons, and energy obtained from the hydrolysis of ATP. Mo-dependent nitrogenase is a symmetric dimer, with each half comprising an ATP-dependent reductase, termed the Fe Protein, and a catalytic protein, known as the MoFe protein, which hosts the electron transfer P-cluster and the active-site metal cofactor (FeMo-co). A series of synchronized events for the electron transfer have been characterized experimentally, in which electron delivery is coupled to nucleotide hydrolysis and regulated by an intricate allosteric network. We report a graph theory analysis of the mechanical coupling in the nitrogenase complex as a key step to understanding the dynamics of allosteric regulation of nitrogen reduction. This analysis shows that regions near the active sites undergo large-scale, large-amplitude correlated motions that enable communications within each half and between the two halves of the complex. Computational predictions of mechanically regions were validated against an analysis of the solution phase dynamics of the nitrogenase complex via hydrogen-deuterium exchange. These regions include the P-loops and the switch regions in the Fe proteins, the loop containing the residue β-188Ser adjacent to the P-cluster in the MoFe protein, and the residues near the protein-protein interface. In particular, it is found that: (i) within each Fe protein, the switch regions I and II are coupled to the [4Fe-4S] cluster; (ii) within each half of the complex, the switch regions I and II are coupled to the loop containing β-188Ser; (iii) between the two halves of the complex, the regions near the nucleotide binding pockets of the two Fe proteins (in particular the P-loops, located over 130 Å apart) are also mechanically coupled. Notably, we found that residues next to the P-cluster (in particular the loop containing β-188Ser) are important for communication between the two halves.

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“…The Gaussian Network Model (GNM) is the most minimalist isotropic elastic network model of Cα atoms with harmonic interactions for the dynamics of proteins and their complexes 44, 45 . GNM-based TE calculations 46, 47 reveal causal interrelations of residues in a given structural topology by considering a certain time delay τ between residue fluctuations ΔR i (t) of residue i at time t and ΔR j (t+ τ ) of residue j at time t+ τ . Using these fluctuations, TE(i,j) ( τ ) provides an estimate for the direction of information flow from residue i to residue j in time delay τ ; i.e.…”

Section: Methodsmentioning

confidence: 99%

“…GNM decomposes the motions into a spectrum of dynamic modes, from global/slow (low frequency) modes to local/fast (high frequency) modes. TE values in Equation 1 could be calculated using all or a subgroup of dynamic modes 47 . As global modes of motion are highly relevant for functional dynamics 48 , here we considered the slowest end of the dynamic mode spectrum with and without the slowest mode; average ten slowest and average two to ten slowest dynamic modes.…”

Section: Methodsmentioning

confidence: 99%

Structural insight into host plasma membrane association and assembly of HIV-1 Matrix protein

Çi̇ftçi̇

Tateishi

Koiwai

et al. 2021

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HIV-1 continues to be a global health concern since AIDS was first recognized by the World Health Organization (WHO). It is estimated that there were 38 million people infected with HIV-1 and 1.5 million deaths in 2019 alone. A better understanding of the details of the HIV late-stage life cycle, involving Pr55Gag attachment to the membrane for the further oligomerization to release virion, will provide us new avenues for potential treatment. Inositol hexakisphosphate (IP6) is an abundant endogenous cyclitol molecule and its binding was linked to the oligomerization of Pr55Gag via the MA domain. However, the binding site of IP6 on MA was unknown and the structural details of this interaction were missing. Here, we present three high-resolution crystal structures of the MA domain in complex with IP6 molecules to reveal its binding mode. Additionally, extensive Differential Scanning Fluorimetry analysis combined with cryo- and ambient-temperature X-ray crystallography and computational biology identify the key residues that participate in IP6 binding. Our data provide novel insights about the multilayered HIV-1 virion assembly process that involves the interplay of IP6 with PIP2, a phosphoinositide essential for the membrane binding of Pr55Gag. IP6 and PIP2 have neighboring alternate binding sites within the same highly basic region (residues 18-33). This indicates that IP6 and PIP2 bindings are not mutually exclusive and may play a key role in coordinating virion particles' membrane localization. Based on our three different IP6-MA complex crystal structures, we propose a new model that involves the IP6 coordination of the oligomerization of outer MA and inner CA domain 2D layers during assembly and budding.

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Distinct Allosteric Networks Underlie Mechanistic Speciation of ABC Transporters

Cited by 25 publications

References 71 publications

Structures of ABC transporters: handle with care

Structures of ABC transporters: handle with care

Mechanical coupling in the nitrogenase complex

Structural insight into host plasma membrane association and assembly of HIV-1 Matrix protein

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