Three-dimensional domain swapping as a mechanism to lock the active conformation in a super-active octamer of SARS-CoV main protease

Zhang, Shengnan; Zhong, Nan; X, Fei; Xue, Kang; Ren, Xiaobai; Chen, Jiaxuan; Jin, Changwen; Lou, Zhiyong; Xia, Bin

doi:10.1007/s13238-010-0044-8

Cited by 43 publications

(55 citation statements)

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“…1) (21). We have also demonstrated that the mature protein of the main protease can assemble into a super-active stable octamer due to 3D domain swapping of its C-terminal domain (22). This stable octameric main protease is constantly active since each subunit is locked into the active conformation, unlike the active dimeric enzyme, which is in equilibrium with the inactive monomer.…”

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confidence: 75%

Foldon unfolding mediates the interconversion between M^pro-C monomer and 3D domain-swapped dimer

Xue

Zhong

Zou

et al. 2012

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

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The C-terminal domain (M pro -C) of SARS-CoV main protease adopts two different fold topologies, a monomer and a 3D domainswapped dimer. Here, we report that M pro -C can reversibly interconvert between these two topological states under physiological conditions. Although the swapped α 1 -helix is fully buried inside the protein hydrophobic core, the interconversion of M pro -C is carried out without the hydrophobic core being exposed to solvent. The 3D domain swapping of M pro -C is activated by an order-to-disorder transition of its C-terminal α 5 -helix foldon. Unfolding of this foldon promotes self-association of M pro -C monomers and functions to mediate the 3D domain swapping, without which M pro -C can no longer form the domain-swapped dimer. Taken together, we propose that there exists a special dimeric intermediate enabling the protein core to unpack and the α 1 -helices to swap in a hydrophobic environment, which minimizes the energy cost of the 3D domainswapping process.NMR | protein folding 3D domain swapping is a unique mechanism for protein dimerization or oligomerization (1, 2). Through exchanging identical structure elements, two or more molecules of the same protein can form a dimer or higher order oligomer with tight binding interface. In recent years, more and more evidences revealed that 3D domain swapping is involved in protein function regulation (2, 3). Most importantly, 3D domain swapping is indicated to be a mechanism for proteins to form aggregates, fibrils, and amyloids, some of which are associated with neurodegenerative diseases (4, 5).Most domain-swapped dimers were obtained through nonphysiological treatments (2), such as low pH, high temperature, crystallization, lyopholization, or freezing. In some cases, slow interconversion (days to months) between a monomeric protein and its domain-swapped dimer was observed under physiological or nondenaturing conditions (6-12), while the process could be speed up by changing conditions favoring unfolding (2, 12). For example, the monomer and domain-swapped dimer of cyanovirin-N was reported to be in apparent equilibrium (half conversion time is about 10 h) at 38°C while its T m is 60°C (8). Similar phenomena were observed for GB1 (11), and p13suc1 (12), etc. Although the mechanism for 3D domain swapping remains unclear, it is commonly believed that unfolding of the monomeric protein is necessary for it to release the domains to be swapped (13). For proteins that swap an independently folded domain, it is proposed that the folded monomer is first converted to an "open monomer" in which the swapped domain is detached from the rest of the protein, followed by domain-swapped dimer formation (7,14,15). As most proteins swap only a few secondary structural elements that do not fold into an independent domain, it is proposed that these proteins must unfold substantially during the domain swapping process (12,(16)(17)(18). For proteins to undergo spontaneous interconversion under physiological or nondenaturing conditions (6-12), either full unfoldin...

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confidence: 75%

Foldon unfolding mediates the interconversion between M^pro-C monomer and 3D domain-swapped dimer

Xue

Zhong

Zou

et al. 2012

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

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“…The critical role of the first seven residues at the N terminus in dimerization and its close proximity to the active site results in this enzyme to be an obligate dimer (Anand et al, 2002), although modification of the termini appears to modulate higher order oligomerization (Zhang et al, 2010). Deletion of the first five amino acid residues results in complete inactivation of this enzyme.…”

Section: Nsp5mentioning

confidence: 99%

Bioinformatics and functional analyses of coronavirus nonstructural proteins involved in the formation of replicative organelles

Neuman

2016

Antiviral Research

107

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Replication of eukaryotic positive-stranded RNA viruses is usually linked to the presence of membrane-associated replicative organelles. The purpose of this review is to discuss the function of proteins responsible for formation of the coronavirus replicative organelle. This will be done by identifying domains that are conserved across the order Nidovirales, and by summarizing what is known about function and structure at the level of protein domains.

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“…The critical role of the first seven residues at the N terminus in dimerization and its close proximity to the active site results in this enzyme to be an obligate dimer, although modification of the termini appears to modulate higher order oligomerization (Zhang et al, 2010). Deletion of the first five amino acids results in complete inactivation of this enzyme.…”

Section: Functionmentioning

confidence: 99%

“…Many excellent and exhaustive studies have based this mechanism of catalysis and the structure of the catalytic site architecture to design several different classes of peptidomimetic inhibitors targeted against M pro of coronaviruses (including SARS) and other pathogenic viruses. Several M pro inhibitors have also been structurally characterized (Akaji et al, 2011;Bacha et al, 2008;Chu et al, 2006;Chuck et al, 2013;Grum-Tokars et al, 2008;Lee et al, 2007;Lee et al, 2009;Lee et al, 2005;Shan and Xu, 2005;Shao et al, 2007;Turlington et al, 2013;Verschueren et al, 2008;Wei et al, 2006;Yang et al, 2006;Yang et al, 2003;Yang et al, 2007;Zhang et al, 2010;Zhu et al, 2011).…”

Section: Functionmentioning

confidence: 99%

Atlas of coronavirus replicase structure

et al. 2014

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The international response to SARS-CoV has produced an outstanding number of protein structures in a very short time. This review summarizes the findings of functional and structural studies including those derived from cryoelectron microscopy, small angle X-ray scattering, NMR spectroscopy, and X-ray crystallography, and incorporates bioinformatics predictions where no structural data is available. Structures that shed light on the function and biological roles of the proteins in viral replication and pathogenesis are highlighted. The high percentage of novel protein folds identified among SARS-CoV proteins is discussed.

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Three-dimensional domain swapping as a mechanism to lock the active conformation in a super-active octamer of SARS-CoV main protease

Abstract: ABSTRACT

Cited by 43 publications

References 55 publications

Foldon unfolding mediates the interconversion between M^pro-C monomer and 3D domain-swapped dimer

Foldon unfolding mediates the interconversion between M^pro-C monomer and 3D domain-swapped dimer

Bioinformatics and functional analyses of coronavirus nonstructural proteins involved in the formation of replicative organelles

Atlas of coronavirus replicase structure

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Three-dimensional domain swapping as a mechanism to lock the active conformation in a super-active octamer of SARS-CoV main protease

Abstract: ABSTRACT

Cited by 43 publications

References 55 publications

Foldon unfolding mediates the interconversion between Mpro-C monomer and 3D domain-swapped dimer

Foldon unfolding mediates the interconversion between Mpro-C monomer and 3D domain-swapped dimer

Bioinformatics and functional analyses of coronavirus nonstructural proteins involved in the formation of replicative organelles

Atlas of coronavirus replicase structure

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Foldon unfolding mediates the interconversion between M^pro-C monomer and 3D domain-swapped dimer

Foldon unfolding mediates the interconversion between M^pro-C monomer and 3D domain-swapped dimer