Journal:Acta Cryst D:S2059798318015322
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<StructureSection load='' size='450' side='right' scene='80/800124/Cv/1' caption=''> | <StructureSection load='' size='450' side='right' scene='80/800124/Cv/1' caption=''> | ||
| - | === Structure of ISG15 from the bat species Myotis davidii and the impact of interdomain ISG15 interactions on viral protein engagement === | + | === Structure of ISG15 from the bat species ''Myotis davidii'' and the impact of interdomain ISG15 interactions on viral protein engagement === |
<big>Caroline Langley, Octavia Goodwin, John V. Dzimianski, Courtney M. Daczkowski and Scott D. Pegan</big> <ref>doi 10.1107/S2059798318015322</ref> | <big>Caroline Langley, Octavia Goodwin, John V. Dzimianski, Courtney M. Daczkowski and Scott D. Pegan</big> <ref>doi 10.1107/S2059798318015322</ref> | ||
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Ubiquitin-like interferon-stimulated gene product 15 (ISG15) is a key modulator of interferon responses involved in the innate immune system. This 15 kDa protein is comprised of two ubiquitin (Ub)-like β-grasp three-dimensional folds. Post-translational modifications of viral proteins introduced by ISG15 have been directly observed to affect the function of numerous viral proteins. While ubiquitin is essentially identical across all animals, comparison of ISG15 across species reveals they are relatively divergent, with sequence identity dropping as low as ~58% among mammals. These ISG15 species-species differences have also long been shown to impact viral deISGylase function. | Ubiquitin-like interferon-stimulated gene product 15 (ISG15) is a key modulator of interferon responses involved in the innate immune system. This 15 kDa protein is comprised of two ubiquitin (Ub)-like β-grasp three-dimensional folds. Post-translational modifications of viral proteins introduced by ISG15 have been directly observed to affect the function of numerous viral proteins. While ubiquitin is essentially identical across all animals, comparison of ISG15 across species reveals they are relatively divergent, with sequence identity dropping as low as ~58% among mammals. These ISG15 species-species differences have also long been shown to impact viral deISGylase function. | ||
| - | Recently, the structure of the first non-human ISG15 originating from mouse suggested that human structures of ISG15s may not be reflective of other species. Here, the | + | Recently, the structure of the first non-human ISG15 originating from mouse suggested that human structures of ISG15s may not be reflective of other species. Here, the structure of ISG15 from the bat species ''Myotis davidii'' solved to 1.37 Å is reported ([[6mdh]]). Comparison of this ISG15 structure with those of human and mouse not only underscores the structural impact of ISG15 species-species differences, but also highlights a conserved hydrophobic motif formed between the two domains of ISG15. Using papain-like deISGylase from the severe acute respiratory coronavirus as a probe, the biochemical importance of this interface and its species-species variances on ISG15-protein engagements was illuminated. |
| - | <scene name='80/800124/Cv/ | + | <scene name='80/800124/Cv/16'>Overlay of ISG15s from bat, mouse, and human</scene>. Structures of <span style="color:lime;background-color:black;font-weight:bold;">hISG15 (green;</span> [[1z2m]]), <font color='magenta'><b>mISG15 (magenta;</b></font> [[5chf]]), and <span style="color:deepskyblue;background-color:black;font-weight:bold;">bISG15 (blue</span> [[6mdh]]) are superimposed using the least squared fit of residues comprising the C-terminal domain on each respective protein. <scene name='80/800124/Cv/6'>Click here to see animation of this scene</scene>. <jmol><jmolButton> |
<script>if (_animating); anim pause;set echo bottom left; color echo white; font echo 20 sansserif;echo Animation Paused; else; anim resume; set echo off;endif;</script> | <script>if (_animating); anim pause;set echo bottom left; color echo white; font echo 20 sansserif;echo Animation Paused; else; anim resume; set echo off;endif;</script> | ||
<text>Toggle Animation</text> | <text>Toggle Animation</text> | ||
</jmolButton></jmol> | </jmolButton></jmol> | ||
| - | Apart from the surface differences between bISG15 and those of other structurally solved ISG15, noticeable tertiary differences between these ISG15 structures were observed. When the ISG15s from bat, mouse and human sources are overlaid using a least squared fit of residues comprising the C-terminal domain of each structure, a noticeable difference in the twist about the C-terminal and N-terminal domains becomes apparent. Closer investigation into the interface between the domains of these three proteins reveals the potential molecular drivers for these differences. <scene name='80/800124/Cv/13'>Close up view of the hinge region of ISG15 from bat</scene>. As with previous ISG15 structures, there is an apparent hydrophobic interaction between the N- and C-terminal domains of bISG15. The C-terminal side of the interaction is facilitated by Leu81, Leu99, and Pro143 with the N-terminal side principally using Phe40 supported in its position by Pro38. With the exception of Pro38 that is a histidine residue in hISG15, all these positions are conserved between bISG15 and those of ISG15 originating from mice and humans. However, just as there was a noticeable difference between the hinge regions of mISG15 and hISG15, there is one for bISG15. Specifically, bISG15’s hinge region possesses a type I reverse turn that separates bISG15 from mISG15 and hISG15. Unlike the hinge region of other ISG15s, reverse turn directionally alters the chain’s direction facilitating bISG15 domain-domain orientation observed. <scene name='80/800124/Cv/9'>This turn is facilitated by Ser76, Cys77, Asp78, and Arg79</scene>. This SCDR primary sequence motif is NCSE in mice and KCDE in humans. With mISG15 and hISG15 lacking the serine hydroxyl group – aspartic carboxylic acid interaction, mISG15 and hISG15 are not able to replicate this tight turn that is present in bISG15. However, other mammal ISG15s, such as that of the white tooth shrew, do have the biochemical ability to form the turn. This suggests that this motif is not just solely restricted to bat ISG15s, but could be present in other species ISG15s. | + | Apart from the surface differences between bISG15 and those of other structurally solved ISG15, noticeable tertiary differences between these ISG15 structures were observed. When the ISG15s from bat, mouse and human sources are overlaid using a least squared fit of residues comprising the C-terminal domain of each structure, a noticeable difference in the twist about the C-terminal and N-terminal domains becomes apparent. Closer investigation into the interface between the domains of these three proteins reveals the potential molecular drivers for these differences. |
| + | *<scene name='80/800124/Cv/13'>Close up view of the hinge region of ISG15 from bat</scene>. | ||
| + | *<scene name='80/800124/Cv/12'>Close up view of the hinge region of ISG15s from mouse</scene>. | ||
| + | *<scene name='80/800124/Cv/11'>Close up view of the hinge region of ISG15s from human</scene>. | ||
| + | As with previous ISG15 structures, there is an apparent hydrophobic interaction between the N- and C-terminal domains of bISG15. The C-terminal side of the interaction is facilitated by Leu81, Leu99, and Pro143 with the N-terminal side principally using Phe40 supported in its position by Pro38. With the exception of Pro38 that is a histidine residue in hISG15, all these positions are conserved between bISG15 and those of ISG15 originating from mice and humans. However, just as there was a noticeable difference between the hinge regions of mISG15 and hISG15, there is one for bISG15. Specifically, bISG15’s hinge region possesses a type I reverse turn that separates bISG15 from mISG15 and hISG15. Unlike the hinge region of other ISG15s, reverse turn directionally alters the chain’s direction facilitating bISG15 domain-domain orientation observed. <scene name='80/800124/Cv/9'>This turn is facilitated by Ser76, Cys77, Asp78, and Arg79</scene>. This SCDR primary sequence motif is NCSE in mice and KCDE in humans. With mISG15 and hISG15 lacking the serine hydroxyl group – aspartic carboxylic acid interaction, mISG15 and hISG15 are not able to replicate this tight turn that is present in bISG15. | ||
| + | *<scene name='80/800124/Cv/14'>Lack of reverse turn in mISG15</scene>. | ||
| + | *<scene name='80/800124/Cv/15'>Lack of reverse turn in hISG15</scene>. | ||
| + | However, other mammal ISG15s, such as that of the [https://en.wikipedia.org/wiki/White-toothed_shrew white tooth shrew], do have the biochemical ability to form the turn. This suggests that this motif is not just solely restricted to bat ISG15s, but could be present in other species ISG15s. | ||
| - | + | '''PDB reference:''' X-ray crystal structure of ISG15 from ''Myotis davidii'', [[6mdh]]. | |
| - | + | ||
<b>References</b><br> | <b>References</b><br> | ||
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