Overlap of cargo binding sites on myosin V coordinates the inheritance of diverse cargoes

Eves, P. Taylor; Jin, Yui; Brunner, Matthew J.; Weisman, Lois S.

doi:10.1083/jcb.201201024

Cited by 80 publications

(122 citation statements)

References 48 publications

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“…S8). Previous studies of yeast myo2p suggested the site 2 in yeast MyoV is involved in binding to several target proteins; many of these proteins do not have corresponding counterparts in mammals (7,8), indicating that both MyoV-GTD and its cargos undergo extensive changes during evolution. Despite of the high-sequence similarity between MyoVa and Vb, neither RILPL2 nor MLPH shows specific binding to MyoVb-GTD, indicating exquisite cargo-binding specificities of the closely related MyoV paralogs.…”

Section: Discussionmentioning

confidence: 99%

“…Several cargo-binding sites have been identified in yeast myo2p via structure-based, mutagenesis-based experiments (7,8). Interestingly, the cargo-binding surface in subdomain I of myo2p, which is critical for binding to vacuole-or mitochondrialspecific cargos, partially overlaps with the corresponding MLPHbinding surface on MyoVa (Fig.…”

Section: Myova-gtd Uses Different Sites To Interact With Rilpl2 and Mmentioning

confidence: 99%

“…Accumulating evidences indicate that the GTD is the major cargobinding region in MyoV. In S. cerevisiae, the myo2p-binding sites of organelle and vesicle-specific adaptors have been mapped onto the GTD region (7,8). In mammals, MyoV-GTD directly interacts with several adaptor proteins, including melanophilin (MLPH) (9)(10)(11), Rab interacting lysosomal protein-like 2 (RILPL2) (12), and granuphilin (13) for MyoVa, and Rab11-family interacting protein 2 (14) for MyoVb.…”

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confidence: 99%

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Structural basis of cargo recognitions for class V myosins

Wei

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

101

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Class V myosins (MyoV), the most studied unconventional myosins, recognize numerous cargos mainly via the motor's globular tail domain (GTD). Little is known regarding how MyoV-GTD recognizes such a diverse array of cargos specifically. Here, we solved the crystal structures of MyoVa-GTD in its apo-form and in complex with two distinct cargos, melanophilin and Rab interacting lysosomal protein-like 2. The apo-MyoVa-GTD structure indicates that most mutations found in patients with Griscelli syndrome, microvillus inclusion disease, or cancers or in "dilute" rodents likely impair the folding of GTD. The MyoVa-GTD/cargo complex structure reveals two distinct cargo-binding surfaces, one primarily via charge-charge interaction and the other mainly via hydrophobic interactions. Structural and biochemical analysis reveal the specific cargo-binding specificities of various isoforms of mammalian MyoV as well as very different cargo recognition mechanisms of MyoV between yeast and higher eukaryotes. The MyoVa-GTD structures resolved here provide a framework for future functional studies of vertebrate class V myosins.

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Section: Discussionmentioning

confidence: 99%

Section: Myova-gtd Uses Different Sites To Interact With Rilpl2 and Mmentioning

confidence: 99%

mentioning

confidence: 99%

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Structural basis of cargo recognitions for class V myosins

Wei

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

101

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“…It is now known that these myosins, (e.g., in classes, I, V, VI, VII, IX and X) contain cargo-binding domains in their tail regions, which bind select adaptor proteins that target these myosins to specialized compartments/organelles within the cell where they perform specific functions. In the case of myosin V and VI there is structural data available on the cargo binding interfaces involved [86][87][88], which could serve as templates to design specific inhibitors. Thus, by targeting unique myosin-adaptor protein interactions, one could manipulate a specific adaptor protein-related motor function linked to distinct step(s) along a pathway within specialized cells.…”

Section: Future Perspectivementioning

confidence: 99%

Small-Molecule Inhibitors of Myosin Proteins

et al. 2012

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Advances in screening and computational methods have enhanced recent efforts to discover/ design small-molecule protein inhibitors. One attractive target for inhibition is the myosin family of motor proteins. Myosins function in a wide variety of cellular processes, from intracellular trafficking to cell motility, and are implicated in several human diseases (e.g., cancer, hypertrophic cardiomyopathy, deafness and many neurological disorders). Potent and selective myosin inhibitors are, therefore, not only a tool for understanding myosin function, but are also a resource for developing treatments for diseases involving myosin dysfunction or overactivity. This review will provide a brief overview of the characteristics and scientific/therapeutic applications of the presently identified small-molecule myosin inhibitors before discussing the future of myosin inhibitor and activator design.The identification and characterization of pharmacological compounds that inhibit the functional activity of one or more specific proteins or processes has been the subject of much scientific investigation. On a basic science level, these membrane-permeable compounds provide the scientific community with a tool for the targeted and functional inhibition of a given protein in the cell; a potent means of evaluating the intracellular functions of that protein [1,2]. From a biomedical standpoint, the characterization of these small-molecule inhibitors affords an opportunity for the development of novel disease treatments centering on the repression of an offensive molecule or the reversal of its downstream effects [3][4][5].At present, several complementary methods for obtaining suitable small-molecule inhibitors of specific proteins exist. Traditional methods in inhibitor discovery involve the systematic testing of a series of chemically synthesized or naturally occurring compounds. Advances in robotics and data processing have made it possible to use high-throughput screens to test libraries of thousands or even millions of potential drugs for their ability to inhibit the function of a specific protein in a targeted biochemical or cellular assay [6][7][8]. These inhibitor discovery processes are complemented by more precise methods in small-molecule inhibitor design. Structure-based methods rely on the use of x-ray crystallographic or NMRbased structures of a protein of interest to design small molecules likely to bind and inhibit protein function [9,10]. Computer-aided inhibitor design uses computational methods to optimize potential inhibitors identified by screening or structure-based methods, to virtually © 2013 Folma Buss * Author for correspondence: Tel.: +44 1223 763348, Fax: +44 1223 762640, fb207@cam.ac.uk. Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance w...

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“…25,26 Two additional proteins, Ypt11 and Mmr1, interact with the cargo-binding domain on the Myo2 tail and participate in mitochondrial inheritance. 27,28 A recent study using live cell microscopy revealed that Num1 is required for attachment of mitochondria to the cell cortex and retention in mother cells, and that expression of chimeric plasma membrane tethers rescued mitochondrial fission defects in ∆num1 and ∆mdm36 mutants. 20 The pattern of mitochondrial distribution is closely linked to the cell cycle, and is demonstrated by time-lapse imaging of mitochondria in the cell cycle of budding yeast.…”

Section: Budding Yeastmentioning

confidence: 99%