Role of the leucine-rich repeat protein kinase 2 C-terminal tail in domain cross-talk.

Autor:	Sharma PK; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0652, U.S.A., Weng JH; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0652, U.S.A., Manschwetus JT; Department of Biochemistry, University of Kassel, Heinrich-Plett-Str. 40, 34132 Kassel, Hessen, Germany., Wu J; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0652, U.S.A., Ma W; Department of Physics, University of Vermont, Burlington, Vermont., Herberg FW; Department of Biochemistry, University of Kassel, Heinrich-Plett-Str. 40, 34132 Kassel, Hessen, Germany., Taylor SS; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0652, U.S.A.; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0652, U.S.A.
Jazyk:	angličtina
Zdroj:	The Biochemical journal [Biochem J] 2024 Feb 21; Vol. 481 (4), pp. 313-327.
DOI:	10.1042/BCJ20230477
Abstrakt:	Leucine-rich repeat protein kinase 2 (LRRK2) is a multi-domain protein encompassing two of biology's most critical molecular switches, a kinase and a GTPase, and mutations in LRRK2 are key players in the pathogenesis of Parkinson's disease (PD). The availability of multiple structures (full-length and truncated) has opened doors to explore intra-domain cross-talk in LRRK2. A helix extending from the WD40 domain and stably docking onto the kinase domain is common in all available structures. This C-terminal (Ct) helix is a hub of phosphorylation and organelle-localization motifs and thus serves as a multi-functional protein : protein interaction module. To examine its intra-domain interactions, we have recombinantly expressed a stable Ct motif (residues 2480-2527) and used peptide arrays to identify specific binding sites. We have identified a potential interaction site between the Ct helix and a loop in the CORB domain (CORB loop) using a combination of Gaussian accelerated molecular dynamics simulations and peptide arrays. This Ct-Motif contains two auto-phosphorylation sites (T2483 and T2524), and T2524 is a 14-3-3 binding site. The Ct helix, CORB loop, and the CORB-kinase linker together form a part of a dynamic 'CAP' that regulates the N-lobe of the kinase domain. We hypothesize that in inactive, full-length LRRK2, the Ct-helix will also mediate interactions with the N-terminal armadillo, ankyrin, and LRR domains (NTDs) and that binding of Rab substrates, PD mutations, or kinase inhibitors will unleash the NTDs. (© 2024 The Author(s).)
Databáze:	MEDLINE
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