Principles of unconventional Myosin function and targeting

Department of Biochemistry, Stanford University, Stanford, California 94305, USA.
Annual Review of Cell and Developmental Biology (Impact Factor: 20.24). 05/2011; 27:133-55. DOI: 10.1146/annurev-cellbio-100809-151502
Source: PubMed

ABSTRACT Unconventional myosins are a superfamily of actin-based motors implicated in diverse cellular processes. In recent years, much progress has been made in describing their biophysical properties, and headway has been made into analyzing their cellular functions. Here, we focus on the principles that guide in vivo motor function and targeting to specific cellular locations. Rather than describe each motor comprehensively, we outline the major themes that emerge from research across the superfamily and use specific examples to illustrate each. In presenting the data in this format, we seek to identify open questions in each field as well as to point out commonalities between them. To advance our understanding of myosins' roles in vivo, clearly we must identify their cellular cargoes and the protein complexes that regulate motor attachment to fully appreciate their functions on the cellular and developmental levels.

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    • "The MLC is an essential component of this family that is responsible for cytoskeletal dynamics for communication, migration and cell division (Sellers, 2000; Redowicz, 2007; Hartman et al., 2011) Myosin has an important role in the processes related to structural stabilization and cellular dynamics, rendering the cell membrane resistant to potential deformations. Furthermore, myosin is involved in actin-enabled motor mechanisms and the organization of actin in the intracellular space (Hartman et al., 2011; Kneussel and Wagner, 2013). FLNa, a substrate of PAK, is also an important cellular structural component. "
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    ABSTRACT: PAKs are a family of serine/threonine protein kinases activated by small GTPases of the Rho family, including Rac and Cdc42, and are categorized into group I (isoforms 1, 2 and 3) and group II (isoforms 4, 5 and 6). PAK1 and PAK3 are critically involved in biological mechanisms associated with neurodevelopment, neuroplasticity and maturation of the nervous system, and changes in their activity have been detected in pathological disorders, such as Alzheimer's disease, Huntington's disease and mental retardation. The group I PAKs have been associated with neurological processes due to their involvement in intracellular mechanisms that result in molecular and cellular morphological alterations that promote cytoskeletal outgrowth, increasing the efficiency of synaptic transmission. Their substrates in these processes include other intracellular signaling molecules, such as Raf, Mek and LIMK, as well as other components of the cytoskeleton, such as MLC and FLNa. In this review, we describe the characteristics of group I PAKs, such as their molecular structure, mechanisms of activation and importance in the neurobiological processes involved in synaptic plasticity.
    Journal of Physiology-Paris 08/2014; 108(4-6). DOI:10.1016/j.jphysparis.2014.08.007 · 2.35 Impact Factor
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    • "The first two act as motors on microtubule filaments, while myosins function on actin (Vale 2003). Myosins participate in a variety of cellular processes, including cytokinesis , organellar transport, cell polarization, transcriptional regulation, intracellular transport, and signal transduction (Hofmann et al. 2009; Bloemink and Geeves 2011; Hartman et al. 2011). They bind to filamentous actin and produce physical forces by hydrolyzing ATP and converting chemical energy into mechanical force (Hartman and Spudich 2012). "
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    ABSTRACT: Myosins are key components of the eukaryotic cytoskeleton, providing motility for a broad diversity of cargoes. Therefore, understanding the origin and evolutionary history of myosin classes is crucial to address the evolution of eukaryote cell biology. Here, we revise the classification of myosins using an updated taxon sampling that includes newly or recently sequenced genomes and transcriptomes from key taxa. We performed a survey of eukaryotic genomes and phylogenetic analyses of the myosin gene family, reconstructing the myosin toolkit at different key nodes in the eukaryotic tree of life. We also identified the phylogenetic distribution of myosin diversity in terms of number of genes, associated protein domains and number of classes in each taxa. Our analyses show that new classes (i.e. paralogs) and domain architectures were continuously generated throughout eukaryote evolution, with a significant expansion of myosin abundance and domain architectural diversity at the stem of Holozoa, predating the origin of animal multicellularity. Indeed, single-celled holozoans have the most complex myosin complement among eukaryotes, with paralogs of most myosins previously considered animal-specific. We recover a dynamic evolutionary history, with several lineage-specific expansions (e.g. the 'myosin III-like' gene family diversification in choanoflagellates), convergence in protein domain architectures (e.g. fungal and animal chitin synthase myosins), and important secondary losses. Overall, our evolutionary scheme demonstrates that the ancestral eukaryote likely had a complex myosin repertoire that included six genes with different protein domain architectures. Finally, we provide an integrative and robust classification, useful for future genomic and functional studies on this crucial eukaryotic gene family.
    Genome Biology and Evolution 01/2014; DOI:10.1093/gbe/evu013 · 4.53 Impact Factor
    • "However, loop regions that control functional features, such as actin binding and nucleotide binding, appear to be actually more constrained than the sequences of the rest of the myosin molecule (Goodson et al., 1999). Although the motor domain is structurally conserved throughout the myosin superfamily, critical features of the motor such as the ability to produce force and movement against an external load, processivity of movement, and the regulation of motor activity by ion binding or posttranslational modifications can differ greatly between myosin isoforms (Hartman et al., 2011). Four structural subdomains can be distinguished, the N-terminal subdomain, the upper (U50) and lower (L50) 50 kDa subdomains, and the converter (Figure 1). "
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    ABSTRACT: Aberrant actomyosin interactions contribute to a wide range of pathophysiological conditions including heart failure, neurodegenerative disorders, and tumor growth. Despite surgical, interventional, and pharmacological advances, the burden and economic impact of these diseases remains immense. The initiation and progression of these disorders is frequently found to be a direct consequence of aberrant motile activity, which makes the in-depth investigation of the molecular mechanisms underlying actomyosin-dependent motility a prerequisite for the development of innovative treatment strategies. The present review describes key structural features of the actomyosin system, the basis of chemo-mechanical and allosteric coupling in the myosin motor domain, and molecular engineering and small molecule-based approaches to alter myosin function.
    Structure 11/2013; 21(11):1911-22. DOI:10.1016/j.str.2013.09.015 · 6.79 Impact Factor
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