Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2
Gain-of-function mutations in LRRK2, which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles and activated by Rab29, a Rab guanosine triphosphatase encoded in the PARK16 locus. We present cryo-electron microscopy structures of Rab29-LRRK2 complexes in three oligomeric states, providing key snapshots during LRRK2 recruitment and activation. Rab29 induces an unexpected tetrameric assembly of LRRK2, formed by two kinase-active central protomers and two kinase-inactive peripheral protomers. The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson's disease treatment.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:382 |
|---|---|
| Enthalten in: |
Science (New York, N.Y.) - 382(2023), 6677 vom: 22. Dez., Seite 1404-1411 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhu, Hanwen [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 26.01.2024 Date Revised 13.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1126/science.adi9926 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM366183931 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM366183931 | ||
| 003 | DE-627 | ||
| 005 | 20240313233941.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231227s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1126/science.adi9926 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1326.xml |
| 035 | |a (DE-627)NLM366183931 | ||
| 035 | |a (NLM)38127736 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhu, Hanwen |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2 |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 26.01.2024 | ||
| 500 | |a Date Revised 13.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Gain-of-function mutations in LRRK2, which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles and activated by Rab29, a Rab guanosine triphosphatase encoded in the PARK16 locus. We present cryo-electron microscopy structures of Rab29-LRRK2 complexes in three oligomeric states, providing key snapshots during LRRK2 recruitment and activation. Rab29 induces an unexpected tetrameric assembly of LRRK2, formed by two kinase-active central protomers and two kinase-inactive peripheral protomers. The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson's disease treatment | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Antiparkinson Agents |2 NLM | |
| 650 | 7 | |a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Protein Subunits |2 NLM | |
| 650 | 7 | |a rab GTP-Binding Proteins |2 NLM | |
| 650 | 7 | |a EC 3.6.5.2 |2 NLM | |
| 650 | 7 | |a Rab29 protein, human |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 700 | 1 | |a Tonelli, Francesca |e verfasserin |4 aut | |
| 700 | 1 | |a Turk, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Prescott, Alan |e verfasserin |4 aut | |
| 700 | 1 | |a Alessi, Dario R |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Ji |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Science (New York, N.Y.) |d 1880 |g 382(2023), 6677 vom: 22. Dez., Seite 1404-1411 |w (DE-627)NLM000023450 |x 1095-9203 |7 nnns |
| 773 | 1 | 8 | |g volume:382 |g year:2023 |g number:6677 |g day:22 |g month:12 |g pages:1404-1411 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1126/science.adi9926 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 382 |j 2023 |e 6677 |b 22 |c 12 |h 1404-1411 | ||