A disordered encounter complex is central to the yeast Abp1p SH3 domain binding pathway.
Protein-protein interactions are involved in a wide range of cellular processes. These interactions often involve intrinsically disordered proteins (IDPs) and protein binding domains. However, the details of IDP binding pathways are hard to characterize using experimental approaches, which can rarel...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-09-01
|
| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1007815&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850117689969737728 |
|---|---|
| author | Gabriella J Gerlach Rachel Carrock Robyn Stix Elliott J Stollar K Aurelia Ball |
| author_facet | Gabriella J Gerlach Rachel Carrock Robyn Stix Elliott J Stollar K Aurelia Ball |
| author_sort | Gabriella J Gerlach |
| collection | DOAJ |
| description | Protein-protein interactions are involved in a wide range of cellular processes. These interactions often involve intrinsically disordered proteins (IDPs) and protein binding domains. However, the details of IDP binding pathways are hard to characterize using experimental approaches, which can rarely capture intermediate states present at low populations. SH3 domains are common protein interaction domains that typically bind proline-rich disordered segments and are involved in cell signaling, regulation, and assembly. We hypothesized, given the flexibility of SH3 binding peptides, that their binding pathways include multiple steps important for function. Molecular dynamics simulations were used to characterize the steps of binding between the yeast Abp1p SH3 domain (AbpSH3) and a proline-rich IDP, ArkA. Before binding, the N-terminal segment 1 of ArkA is pre-structured and adopts a polyproline II helix, while segment 2 of ArkA (C-terminal) adopts a 310 helix, but is far less structured than segment 1. As segment 2 interacts with AbpSH3, it becomes more structured, but retains flexibility even in the fully engaged state. Binding simulations reveal that ArkA enters a flexible encounter complex before forming the fully engaged bound complex. In the encounter complex, transient nonspecific hydrophobic and long-range electrostatic contacts form between ArkA and the binding surface of SH3. The encounter complex ensemble includes conformations with segment 1 in both the forward and reverse orientation, suggesting that segment 2 may play a role in stabilizing the correct binding orientation. While the encounter complex forms quickly, the slow step of binding is the transition from the disordered encounter ensemble to the fully engaged state. In this transition, ArkA makes specific contacts with AbpSH3 and buries more hydrophobic surface. Simulating the binding between ApbSH3 and ArkA provides insight into the role of encounter complex intermediates and nonnative hydrophobic interactions for other SH3 domains and IDPs in general. |
| format | Article |
| id | doaj-art-bc9d3728c2b342579d4679813a3d11f9 |
| institution | OA Journals |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2020-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-bc9d3728c2b342579d4679813a3d11f92025-08-20T02:36:02ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582020-09-01169e100781510.1371/journal.pcbi.1007815A disordered encounter complex is central to the yeast Abp1p SH3 domain binding pathway.Gabriella J GerlachRachel CarrockRobyn StixElliott J StollarK Aurelia BallProtein-protein interactions are involved in a wide range of cellular processes. These interactions often involve intrinsically disordered proteins (IDPs) and protein binding domains. However, the details of IDP binding pathways are hard to characterize using experimental approaches, which can rarely capture intermediate states present at low populations. SH3 domains are common protein interaction domains that typically bind proline-rich disordered segments and are involved in cell signaling, regulation, and assembly. We hypothesized, given the flexibility of SH3 binding peptides, that their binding pathways include multiple steps important for function. Molecular dynamics simulations were used to characterize the steps of binding between the yeast Abp1p SH3 domain (AbpSH3) and a proline-rich IDP, ArkA. Before binding, the N-terminal segment 1 of ArkA is pre-structured and adopts a polyproline II helix, while segment 2 of ArkA (C-terminal) adopts a 310 helix, but is far less structured than segment 1. As segment 2 interacts with AbpSH3, it becomes more structured, but retains flexibility even in the fully engaged state. Binding simulations reveal that ArkA enters a flexible encounter complex before forming the fully engaged bound complex. In the encounter complex, transient nonspecific hydrophobic and long-range electrostatic contacts form between ArkA and the binding surface of SH3. The encounter complex ensemble includes conformations with segment 1 in both the forward and reverse orientation, suggesting that segment 2 may play a role in stabilizing the correct binding orientation. While the encounter complex forms quickly, the slow step of binding is the transition from the disordered encounter ensemble to the fully engaged state. In this transition, ArkA makes specific contacts with AbpSH3 and buries more hydrophobic surface. Simulating the binding between ApbSH3 and ArkA provides insight into the role of encounter complex intermediates and nonnative hydrophobic interactions for other SH3 domains and IDPs in general.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1007815&type=printable |
| spellingShingle | Gabriella J Gerlach Rachel Carrock Robyn Stix Elliott J Stollar K Aurelia Ball A disordered encounter complex is central to the yeast Abp1p SH3 domain binding pathway. PLoS Computational Biology |
| title | A disordered encounter complex is central to the yeast Abp1p SH3 domain binding pathway. |
| title_full | A disordered encounter complex is central to the yeast Abp1p SH3 domain binding pathway. |
| title_fullStr | A disordered encounter complex is central to the yeast Abp1p SH3 domain binding pathway. |
| title_full_unstemmed | A disordered encounter complex is central to the yeast Abp1p SH3 domain binding pathway. |
| title_short | A disordered encounter complex is central to the yeast Abp1p SH3 domain binding pathway. |
| title_sort | disordered encounter complex is central to the yeast abp1p sh3 domain binding pathway |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1007815&type=printable |
| work_keys_str_mv | AT gabriellajgerlach adisorderedencountercomplexiscentraltotheyeastabp1psh3domainbindingpathway AT rachelcarrock adisorderedencountercomplexiscentraltotheyeastabp1psh3domainbindingpathway AT robynstix adisorderedencountercomplexiscentraltotheyeastabp1psh3domainbindingpathway AT elliottjstollar adisorderedencountercomplexiscentraltotheyeastabp1psh3domainbindingpathway AT kaureliaball adisorderedencountercomplexiscentraltotheyeastabp1psh3domainbindingpathway AT gabriellajgerlach disorderedencountercomplexiscentraltotheyeastabp1psh3domainbindingpathway AT rachelcarrock disorderedencountercomplexiscentraltotheyeastabp1psh3domainbindingpathway AT robynstix disorderedencountercomplexiscentraltotheyeastabp1psh3domainbindingpathway AT elliottjstollar disorderedencountercomplexiscentraltotheyeastabp1psh3domainbindingpathway AT kaureliaball disorderedencountercomplexiscentraltotheyeastabp1psh3domainbindingpathway |