Integrated regulation of motor-driven organelle transport by scaffolding proteins - PubMed (original) (raw)

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Integrated regulation of motor-driven organelle transport by scaffolding proteins

Meng-meng Fu et al. Trends Cell Biol. 2014 Oct.

Abstract

Intracellular trafficking pathways, including endocytosis, autophagy, and secretion, rely on directed organelle transport driven by the opposing microtubule motor proteins kinesin and dynein. Precise spatial and temporal targeting of vesicles and organelles requires the integrated regulation of these opposing motors, which are often bound simultaneously to the same cargo. Recent progress demonstrates that organelle-associated scaffolding proteins, including Milton/TRAKs (trafficking kinesin-binding protein), JIP1, JIP3 (JNK-interacting proteins), huntingtin, and Hook1, interact with molecular motors to coordinate activity and sustain unidirectional transport. Scaffolding proteins also bind to upstream regulatory proteins, including kinases and GTPases, to modulate transport in the cell. This integration of regulatory control with motor activity allows for cargo-specific changes in the transport or targeting of organelles in response to cues from the complex cellular environment.

Keywords: axonal transport; dynactin; dynein; intracellular trafficking; kinesin; organelle transport.

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Figures

Figure 1. Three current models for the regulation of microtubule motors bound to vesicular and organelle cargo

(A) In the selective recruitment model, only one type of motor, either kinesin (KHC) or dynein-dynactin, are bound to cargo at time. If kinesin is bound, the cargo will move unidirectionally in the anterograde direction toward the plus-end of the microtubule. If dynein-dynactin is bound, the cargo will move unidirectionally in the retrograde direction, toward the microtubule minus-end. (B) In the tug-of-war model, both kinesin and dynein-dynactin motors are bound to the cargo simultaneously. The cargo will move bidirectionally along the microtubule, depending on stochastic variations in the dominant motor type. Note that for simplification, this figure only illustrates one dynein-dynactin complex per vesicle, but that likely 6–8 dynein-dynactin complexes are on each vesicle to reach force balance with one kinesin. (C) In the coordination model, kinesin and dynein are bound to the cargo simultaneously, but the activities of these motors are governed by a scaffolding protein that coordinates the engagement of dynein-dynactin with the autoinhibition of kinesin. Inset – Generalized model for the integration of upstream signaling with downstream motility by scaffolding proteins. Scaffolding proteins interact with vesicle/organelle linker proteins, upstream signaling proteins, and molecular motors, forming an integrated regulatory unit. While scaffolding proteins may also mediate the association of motors with the vesicle or organelle, this is not always the case.

Figure 2. Schematic of binding interactions between bidirectional scaffolding proteins with motor and regulatory proteins

(A-D) One feature of bidirectional scaffolding proteins is that binding domains of anterograde and retrograde motors often are located in close proximity or are overlapping. TRAK binds to Miro, KHC, Miro and p150Glued dynactin. Huntingtin binds to dynein intermediate chain (DIC), optineurin, HAP40, and HAP1, which binds to KLC and p150Glued and can be phosphorylated at S421. JIP3 binds to JNK, ARF6, KHC tail, KLC, and p150Glued. JIP1 binds to JNK, KHC tail and stalk, KLC, and p150Glued. LZ: leucine zipper, JBD: JNK-binding domain; SH3: src homology domain; PTB: phosphotyrosine-binding domain.

Figure I (inset, Box #2). Schematic of binding domains in the p150Glued subunit of dynactin

Several scaffolding proteins share a binding site on C-terminal p150Glued.

Figure II (inset, Outstanding Questions Box). Scaffolding proteins may regulate organelle motility by multiple different mechanisms

The scaffolding proteins known to regulate organelle motility are diverse, and may function through diverse mechanisms. In the motor recruitment model, a soluble scaffolding protein may mediate the association of the motor with its cargo. In a selective activation/inactivation model, scaffolding proteins do not recruit motors to cargo, but function instead to regulate motor activity, selectively activating or inactivating one of the vesicle-bound motors. In a third scaffolding protein activation model, vesicle- bound scaffolding proteins become activated to tightly control activity of vesicle-bound motors.

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Integrated regulation of motor-driven organelle transport by scaffolding proteins - PubMed (original) (raw)