| Structural highlights
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
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