The enigma of the near-symmetry of proteins: Domain swapping

Bonjack-Shterengartz, Maayan; Avnir, David

doi:10.1371/journal.pone.0180030

Cited by 18 publications

(23 citation statements)

References 77 publications

(48 reference statements)

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“…While domain swapping is sometimes functional, and pathological in the case of amyloid proteins, there are many cases where it is an artefact, frequently where a domain has been separated from the rest of a larger protein. These cases usually involve the N-or C-termini, and it has been suggested that this can occur under appropriate conditions for virtually any protein with an unconstrained terminus (Liu & Eisenberg, 2002;Bonjack-Shterengartz & Avnir, 2017;Gronenborn, 2009). …”

Section: Resultsmentioning

confidence: 99%

Cloning, purification and structure determination of the HIV integrase-binding domain of lens epithelium-derived growth factor

et al. 2018

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Lens epithelium-derived growth factor (LEDGF)/p75 is the dominant binding partner of HIV-1 integrase in human cells. The crystal structure of the HIV integrase-binding domain (IBD) of LEDGF has been determined in the absence of ligand. IBD was overexpressed inEscherichia coli, purified and crystallized by sitting-drop vapour diffusion. X-ray diffraction data were collected at Diamond Light Source to a resolution of 2.05 Å. The crystals belonged to space groupP21, with eight polypeptide chains in the asymmetric unit arranged as an unusual octamer composed of four domain-swapped IBD dimers. IBD exists as a mixture of monomers and dimers in concentrated solutions, but the dimers are unlikely to be biologically relevant.

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Section: Resultsmentioning

confidence: 99%

Cloning, purification and structure determination of the HIV integrase-binding domain of lens epithelium-derived growth factor

et al. 2018

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“…Symmetry distortion may provide also a clue on the mechanism of formation of the oligomer. In a previous study 14 we have explored this possibility by focusing on the domain swapping mechanism of dimerization. By this mechanism, two monomeric units swap identical portions, resulting in an interwoven dimer as shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Numerous applications of the CSM methodology all across chemistry have been reported and few examples are collected in the cited references [27][28][29][30] , including biochemistry 14,31,32 and physics 33-37 . types of symmetry analysis. In previous studies 13, 14 we have introduced specific CSM computational tools for the evaluation of the symmetry content, S(G), of proteins. Four variations of which are relevant for this report: The "all-atoms symmetry analysis", "local symmetry analysis", "symmetry maps analysis" and "symmetry spectrum analysis":…”

Section: Methodsmentioning

confidence: 99%

“…The symmetry spectrum, as was introduced in ref. 14 , is a plot of the CSM of the protein, which is constructed as follows (explained for S(C 2 ): A segment of h amino-acids is selected (h is defined as the size of analysis ruler). Then, starting with the 1 st amino-acid in the polypeptide chain of the monomer, the S(C 2 ) value of the first C 2 -symmetry-related segments (1 st -h th amino-acids segments-pair) is calculated, and a first CSM value is obtained.…”

Section: Methodsmentioning

confidence: 99%

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The near-symmetry of protein oligomers: NMR-derived structures

Bonjack

Avnir

2020

Sci Rep

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the majority of oligomeric proteins form clusters which have rotational or dihedral symmetry. Despite the many advantages of symmetric packing, protein oligomers are only nearly symmetric, and the origin of this phenomenon is still in need to be fully explored. Here we apply near-symmetry analyses by the continuous Symmetry Measures methodology of protein homomers to their natural state, namely their structures in solution. NMR-derived structural data serves us for that purpose. We find that symmetry deviations of proteins are by far higher in solution, compared to the crystalline state; that much of the symmetry distortion is due to amino acids along the interface between the subunits; that the distortions are mainly due to hydrophilic amino acids; and that distortive oligomerization processes such as the swap-domain mechanism can be identified by the symmetry analysis. Most of the analyses were carried out on distorted C 2-symmetry dimers, but C 3 and D 2 cases were analyzed as well. our nMR analysis supports the idea that the crystallographic B-factor represents non-classical crystals, in which different conformers pack in the crystal, perhaps from the conformers which the NMR analysis provides. The majority of proteins which form oligomers are organized in quaternary structures which are symmetric at least to some degree 1-3. The most prevalent symmetry point-groups of these oligomers are the cyclic C n and the dihedral D n symmetries. The symmetric assembly of the oligomeric subunits leads to various advantages over asymmetric structure or monomeric form. These include coding efficiency and reduction of synthetic errors, cooperative regulation, increase in stability and formation of lower-energy structures, and minimization of excessive aggregation 2-7. Interestingly, despite these many functional advantages of the symmetric packing, the vast majority of protein oligomers are only nearly symmetric 2,4-6,8-11 , that is, although many oligomeric proteins are classified as 'symmetric' , there are conformational differences between the sequence-identical subunits 2,11. Understanding the origin and role of the asymmetry, is critical for understanding protein functions. In a recent review, Goodsell highlighted the issues around the near symmetry of biological functions in general, and proteins in particular, and pointed to evolutionary processes as lead to symmetry at some degree 1. The distortion from perfect symmetry of proteins is related to several issues, among them are functionality of the protein, thermodynamic considerations, such as enthalpy, entropy and the constant motion of the protein, the asymmetric environment that surrounds the protein, the mechanism of oligomerization, and even experimental conditions 1,9,11-14. Symmetric proteins and their imperfection, have been an ongoing research and some recent studies include global motion patterns of symmetric proteins 15 , how symmetry can compound the effect of point mutations and trigger uncontrolled self-assembly into high-order structures 16 , and how ...

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“…They also found that hydrophilic amino acids are more likely to carry conformational-symmetry distortions [27,28]. In another study, they used the CSM method to locate the hinge region of domain-swapped protein dimers, which is considerably less symmetric than the rest of the protein dimer [29].…”

Section: Introductionmentioning

confidence: 99%

Side chain flexibility and the symmetry of protein homodimers

Shalit

Tuvi-Arad

2020

PLoS ONE

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A comprehensive analysis of crystallographic data of 565 high-resolution protein homodimers comprised of over 250,000 residues suggests that amino acids form two groups that differ in their tendency to distort or symmetrize the structure of protein homodimers. Residues of the first group tend to distort the protein homodimer and generally have long or polar side chains. These include: Lys, Gln, Glu, Arg, Asn, Met, Ser, Thr and Asp. Residues of the second group contribute to protein symmetry and are generally characterized by short or aromatic side chains. These include: Ile, Pro, His, Val, Cys, Leu, Trp, Tyr, Phe, Ala and Gly. The distributions of the continuous symmetry measures of the proteins and the continuous chirality measures of their building blocks highlight the role of side chain geometry and the interplay between entropy and symmetry in dictating the conformational flexibility of proteins.

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The enigma of the near-symmetry of proteins: Domain swapping

Cited by 18 publications

References 77 publications

Cloning, purification and structure determination of the HIV integrase-binding domain of lens epithelium-derived growth factor

Cloning, purification and structure determination of the HIV integrase-binding domain of lens epithelium-derived growth factor

The near-symmetry of protein oligomers: NMR-derived structures

Side chain flexibility and the symmetry of protein homodimers

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