8fo8

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of Rab29-LRRK2 complex in the LRRK2 dimer state

Structural highlights

8fo8 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.88Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RAB7L_HUMAN The small GTPases Rab are key regulators in vesicle trafficking (PubMed:24788816). Essential for maintaining the integrity of the endosome-trans-Golgi network structure (By similarity). Together with LRRK2, plays a role in the retrograde trafficking pathway for recycling proteins, such as mannose 6 phosphate receptor (M6PR), between lysosomes and the Golgi apparatus in a retromer-dependent manner (PubMed:24788816). Recruits LRRK2 to the Golgi complex and stimulates LRRK2 kinase activity (PubMed:29212815). Regulates neuronal process morphology in the intact central nervous system (CNS) (By similarity). May play a role in the formation of typhoid toxin transport intermediates during Salmonella enterica serovar Typhi (S.Typhi) epithelial cell infection (PubMed:22042847).[UniProtKB:Q63481]^[1] ^[2] ^[3]

Publication Abstract from PubMed

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.

Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2.,Zhu H, Tonelli F, Turk M, Prescott A, Alessi DR, Sun J Science. 2023 Dec 22;382(6677):1404-1411. doi: 10.1126/science.adi9926. Epub 2023 , Dec 21. PMID:38127736^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Spano S, Liu X, Galan JE. Proteolytic targeting of Rab29 by an effector protein distinguishes the intracellular compartments of human-adapted and broad-host Salmonella. Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18418-23. doi:, 10.1073/pnas.1111959108. Epub 2011 Oct 31. PMID:22042847 doi:http://dx.doi.org/10.1073/pnas.1111959108
↑ Wang S, Ma Z, Xu X, Wang Z, Sun L, Zhou Y, Lin X, Hong W, Wang T. A role of Rab29 in the integrity of the trans-Golgi network and retrograde trafficking of mannose-6-phosphate receptor. PLoS One. 2014 May 2;9(5):e96242. doi: 10.1371/journal.pone.0096242. eCollection , 2014. PMID:24788816 doi:http://dx.doi.org/10.1371/journal.pone.0096242
↑ Purlyte E, Dhekne HS, Sarhan AR, Gomez R, Lis P, Wightman M, Martinez TN, Tonelli F, Pfeffer SR, Alessi DR. Rab29 activation of the Parkinson's disease-associated LRRK2 kinase. EMBO J. 2018 Jan 4;37(1):1-18. doi: 10.15252/embj.201798099. Epub 2017 Dec 6. PMID:29212815 doi:http://dx.doi.org/10.15252/embj.201798099
↑ Zhu H, Tonelli F, Turk M, Prescott A, Alessi DR, Sun J. Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. Science. 2023 Dec 22;382(6677):1404-1411. PMID:38127736 doi:10.1126/science.adi9926

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8fo8"

Categories: Homo sapiens | Large Structures | Sun J | Zhu H

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8fo8 is ON HOLD
+==Cryo-EM structure of Rab29-LRRK2 complex in the LRRK2 dimer state==
+<StructureSection load='8fo8' size='340' side='right'caption='[[8fo8]], [[Resolution|resolution]] 3.88&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8fo8]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FO8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FO8 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.88&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8fo8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fo8 OCA], [https://pdbe.org/8fo8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fo8 RCSB], [https://www.ebi.ac.uk/pdbsum/8fo8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fo8 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/RAB7L_HUMAN RAB7L_HUMAN] The small GTPases Rab are key regulators in vesicle trafficking (PubMed:24788816). Essential for maintaining the integrity of the endosome-trans-Golgi network structure (By similarity). Together with LRRK2, plays a role in the retrograde trafficking pathway for recycling proteins, such as mannose 6 phosphate receptor (M6PR), between lysosomes and the Golgi apparatus in a retromer-dependent manner (PubMed:24788816). Recruits LRRK2 to the Golgi complex and stimulates LRRK2 kinase activity (PubMed:29212815). Regulates neuronal process morphology in the intact central nervous system (CNS) (By similarity). May play a role in the formation of typhoid toxin transport intermediates during Salmonella enterica serovar Typhi (S.Typhi) epithelial cell infection (PubMed:22042847).[UniProtKB:Q63481]<ref>PMID:22042847</ref> <ref>PMID:24788816</ref> <ref>PMID:29212815</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+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.
-Authors:
+Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2.,Zhu H, Tonelli F, Turk M, Prescott A, Alessi DR, Sun J Science. 2023 Dec 22;382(6677):1404-1411. doi: 10.1126/science.adi9926. Epub 2023 , Dec 21. PMID:38127736<ref>PMID:38127736</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 8fo8" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Sun J]]
+[[Category: Zhu H]]

8fo8

From Proteopedia

Current revision

Cryo-EM structure of Rab29-LRRK2 complex in the LRRK2 dimer state

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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