The cargo adaptor proteins RILPL2 and melanophilin co-regulate myosin-5a motor activity

Cao, Qing-Juan; Zhang, Ning; Zhou, Rui; Yao, Linlin; Li, Xiangdong

doi:10.1074/jbc.ra119.007384

Cited by 16 publications

(13 citation statements)

References 40 publications

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“…Thus, the RH homology domain proteins RILPL1, RILPL2, JIP3 and JIP4 increase their binding to Rab10 upon LRRK2 phosphorylation, whereas MyoVa lacking exon D engages a new partner in the brain and endocrine cells. This may also have cell typespecific implications for MyoVa motor activity (Cao et al, 2019). (A) Immunoblot of reactions containing purified Rab10 and Mst3 kinase, incubated together at 27°C with 2 mM ATP.…”

Section: Discussionmentioning

confidence: 99%

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LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade

et al. 2021

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Activating mutations in LRRK2 kinase causes Parkinson’s disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 and MyoVa relocalize to the peri-centriolar region in a phosphoRab10-dependent manner. PhosphoRab10 retains Myosin Va over pericentriolar membranes as determined by fluorescence loss in photobleaching microscopy. Without pathogenic LRRK2, RILPL2 is not essential for ciliogenesis but RILPL2 over-expression blocks ciliogenesis in RPE cells independent of tau tubulin kinase recruitment to the mother centriole. These experiments show that LRRK2 generated-phosphoRab10 dramatically redistributes a significant fraction of Myosin Va and RILPL2 to the mother centriole in a manner that likely interferes with Myosin Va’s role in ciliogenesis.

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Section: Discussionmentioning

confidence: 99%

“… Waschbüsch et al, 2020 ). Recently, RILPL2 has also been reported to regulate the motor activity of MyoVa ( Cao et al, 2019 ). By binding a myosin motor at one end, and a membrane-anchored Rab at the other end, RILPL2 is an actin-based, motor-adaptor protein.…”

Section: Introductionmentioning

confidence: 99%

LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade

et al. 2021

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“…However, arginine clusters are increasingly being recognized for their contribution to protein complex formation (19)(20)(21). Conformational dynamics of RILPL2 have also previously been observed in its interactions with Rab36 and myosin Va (22). The structures of numerous signaling complexes involving phosphorylated peptides have been determined.…”

Section: Discussionmentioning

confidence: 98%

Dual arginine recognition of LRRK2 phosphorylated Rab GTPases

Waschbüsch

Purlyte

Khan

2021

Biophysical Journal

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Parkinson's-disease-associated LRRK2 is a multidomain Ser/Thr kinase that phosphorylates a subset of Rab GTPases to control their effector functions. Rab GTPases are the prime regulators of membrane trafficking in eukaryotic cells. Rabs exert their biological effects by recruitment of effector proteins to subcellular compartments via their Rab-binding domain (RBD). Effectors are modular and typically contain additional domains that regulate various aspects of vesicle formation, trafficking, fusion, and organelle dynamics. The RBD of effectors is typically an a-helical coiled coil that recognizes the GTP conformation of the switch 1 and switch 2 motifs of Rabs. LRRK2 phosphorylates Rab8a at T72 (pT72) of its switch 2 a-helix. This post-translational modification enables recruitment of RILPL2, an effector that regulates ciliogenesis in model cell lines. A newly identified RBD motif of RILPL2, termed the X-cap, has been shown to recognize the phosphate via direct interactions between an arginine residue (R132) and pT72 of Rab8a. Here, we show that a second distal arginine (R130) is also essential for phospho-Rab binding by RILPL2. Through structural, biophysical, and cellular studies, we find that R130 stabilizes the primary R132:pT72 salt bridge through favorable enthalpic contributions to the binding affinity. These findings may have implications for the mechanism by which LRRK2 activation leads to assembly of phospho-Rab complexes and subsequent control of their membrane trafficking functions in cells.

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“…Thus, the RH homology domain proteins RILPL1, RILPL2, JIP3 and JIP4 increase their binding to Rab10 upon LRRK2 phosphorylation, while MyoVa lacking exon D engages a new partner in the brain and endocrine cells. This may also have cell type-specific implications for MyoVa motor activity (Cao et al, 2019).…”

Section: Rilpl2 Binds Lrrk2-phosphorylated Rab10 With Greater Affinitmentioning

confidence: 99%

LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade

Izumi

Dhekne

Vides

et al. 2020

Preprint

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Activating mutations in LRRK2 kinase cause Parkinson's disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10, and certain tissue-specific Myosin Va isoforms strongly prefer to bind phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 relocalizes to the peri-centriolar region in a phosphoRab10-and Myosin Vadependent manner. In the absence of phosphoRab10, expression of RILPL2 or depletion of Myosin Va increase centriolar RILPL2 levels, and either condition is sufficient to block ciliogenesis in RPE cells. These experiments show that LRRK2 generated phosphoRab10 dramatically redistributes Myosin Va-RILPL2 complexes to the mother centriole, which may sequester Myosin Va and RILPL2 in a manner that blocks their normal roles in ciliogenesis.

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The cargo adaptor proteins RILPL2 and melanophilin co-regulate myosin-5a motor activity

Cited by 16 publications

References 40 publications

LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade

LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade

Dual arginine recognition of LRRK2 phosphorylated Rab GTPases

LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade

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