Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch.
C(2) domains are well characterized as Ca(2+)/phospholipid-binding modules, but little is known about how they mediate protein-protein interactions. In neurons, a Munc13-1 C(2)A-domain/RIM zinc-finger domain (ZF) heterodimer couples synaptic vesicle priming to presynaptic plasticity. We now show tha...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2006-07-01
|
| Series: | PLoS Biology |
| Online Access: | http://europepmc.org/articles/PMC1472246?pdf=render |
| _version_ | 1819153925824053248 |
|---|---|
| author | Jun Lu Mischa Machius Irina Dulubova Han Dai Thomas C Südhof Diana R Tomchick Josep Rizo |
| author_facet | Jun Lu Mischa Machius Irina Dulubova Han Dai Thomas C Südhof Diana R Tomchick Josep Rizo |
| author_sort | Jun Lu |
| collection | DOAJ |
| description | C(2) domains are well characterized as Ca(2+)/phospholipid-binding modules, but little is known about how they mediate protein-protein interactions. In neurons, a Munc13-1 C(2)A-domain/RIM zinc-finger domain (ZF) heterodimer couples synaptic vesicle priming to presynaptic plasticity. We now show that the Munc13-1 C(2)A domain homodimerizes, and that homodimerization competes with Munc13-1/RIM heterodimerization. X-ray diffraction studies guided by nuclear magnetic resonance (NMR) experiments reveal the crystal structures of the Munc13-1 C(2)A-domain homodimer and the Munc13-1 C(2)A-domain/RIM ZF heterodimer at 1.44 A and 1.78 A resolution, respectively. The C(2)A domain adopts a beta-sandwich structure with a four-stranded concave side that mediates homodimerization, leading to the formation of an eight-stranded beta-barrel. In contrast, heterodimerization involves the bottom tip of the C(2)A-domain beta-sandwich and a C-terminal alpha-helical extension, which wrap around the RIM ZF domain. Our results describe the structural basis for a Munc13-1 homodimer-Munc13-1/RIM heterodimer switch that may be crucial for vesicle priming and presynaptic plasticity, uncovering at the same time an unexpected versatility of C(2) domains as protein-protein interaction modules, and illustrating the power of combining NMR spectroscopy and X-ray crystallography to study protein complexes. |
| first_indexed | 2024-12-22T15:12:56Z |
| format | Article |
| id | doaj.art-18a6ba00d1944181976ecb5b658bec83 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-22T15:12:56Z |
| publishDate | 2006-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-18a6ba00d1944181976ecb5b658bec832022-12-21T18:21:49ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852006-07-0147e19210.1371/journal.pbio.0040192Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch.Jun LuMischa MachiusIrina DulubovaHan DaiThomas C SüdhofDiana R TomchickJosep RizoC(2) domains are well characterized as Ca(2+)/phospholipid-binding modules, but little is known about how they mediate protein-protein interactions. In neurons, a Munc13-1 C(2)A-domain/RIM zinc-finger domain (ZF) heterodimer couples synaptic vesicle priming to presynaptic plasticity. We now show that the Munc13-1 C(2)A domain homodimerizes, and that homodimerization competes with Munc13-1/RIM heterodimerization. X-ray diffraction studies guided by nuclear magnetic resonance (NMR) experiments reveal the crystal structures of the Munc13-1 C(2)A-domain homodimer and the Munc13-1 C(2)A-domain/RIM ZF heterodimer at 1.44 A and 1.78 A resolution, respectively. The C(2)A domain adopts a beta-sandwich structure with a four-stranded concave side that mediates homodimerization, leading to the formation of an eight-stranded beta-barrel. In contrast, heterodimerization involves the bottom tip of the C(2)A-domain beta-sandwich and a C-terminal alpha-helical extension, which wrap around the RIM ZF domain. Our results describe the structural basis for a Munc13-1 homodimer-Munc13-1/RIM heterodimer switch that may be crucial for vesicle priming and presynaptic plasticity, uncovering at the same time an unexpected versatility of C(2) domains as protein-protein interaction modules, and illustrating the power of combining NMR spectroscopy and X-ray crystallography to study protein complexes.http://europepmc.org/articles/PMC1472246?pdf=render |
| spellingShingle | Jun Lu Mischa Machius Irina Dulubova Han Dai Thomas C Südhof Diana R Tomchick Josep Rizo Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. PLoS Biology |
| title | Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. |
| title_full | Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. |
| title_fullStr | Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. |
| title_full_unstemmed | Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. |
| title_short | Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. |
| title_sort | structural basis for a munc13 1 homodimer to munc13 1 rim heterodimer switch |
| url | http://europepmc.org/articles/PMC1472246?pdf=render |
| work_keys_str_mv | AT junlu structuralbasisforamunc131homodimertomunc131rimheterodimerswitch AT mischamachius structuralbasisforamunc131homodimertomunc131rimheterodimerswitch AT irinadulubova structuralbasisforamunc131homodimertomunc131rimheterodimerswitch AT handai structuralbasisforamunc131homodimertomunc131rimheterodimerswitch AT thomascsudhof structuralbasisforamunc131homodimertomunc131rimheterodimerswitch AT dianartomchick structuralbasisforamunc131homodimertomunc131rimheterodimerswitch AT joseprizo structuralbasisforamunc131homodimertomunc131rimheterodimerswitch |