Incorporating motility in motor: Role of Hook protein family in

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Incorporating motility in motor: Role of Hook protein family in regulating dynein motility Devashish Dwivedi, Prateek Chawla, and Mahak Sharma Biochemistry, Just Accepted Manuscript • DOI: 10.1021/acs.biochem.8b01065 • Publication Date (Web): 31 Jan 2019 Downloaded from http://pubs.acs.org on February 3, 2019

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Biochemistry

Incorporating motility in motor: Role of Hook protein family in regulating dynein motility Devashish Dwivedi1,#, Prateek Chawla1,# and Mahak Sharma1,2,* 1Department

of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Punjab (India) 2Wellcome #equal

Trust/DBT-India Alliance Intermediate Fellow

contribution

*Corresponding

author: [email protected]

Running title: Hook proteins as activating dynein adaptors Keywords: Motor, Dynein, Dynactin, Hook protein, Adaptor Funding: M.S. acknowledges financial support from the Wellcome Trust/Department of Biotechnology (DBT) India Alliance Intermediate fellowship (IA/I/12/500523) and SERB grant (EMR/2017/002273) and intramural funding support from IISER-Mohali. D.D. acknowledges support from CSIR-UGC and IISER Mohali. P.C. acknowledges support from IISER Mohali.

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Abstract Cytoplasmic dynein is a retrograde microtubule-based motor transporting cellular cargo including organelles, vesicular intermediates, RNA granules and proteins, thus regulating their subcellular distribution and function. Mammalian dynein associates with dynactin, a multisubunit protein complex that is necessary for the processive motility of dynein along the microtubule tracks. Recent studies have shown that the interaction between dynein and dynactin is enhanced in the presence of a coiled-coil activating adaptor protein, which performs a dual function of recruiting dynein-dynactin to their cargoes and inducing superprocessive motility of the motor complex. One such family of coiled-coil activating adaptor proteins is the Hook proteins that are conserved across evolution with three paralogs in case of mammals, namely HOOK1, HOOK2 and HOOK3. This review aims to provide an overview of the Hook protein structure and their cellular functions with emphasis on the recent developments in understanding of their role as activating dynein adaptors.


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Biochemistry

Introduction Microtubule cytoskeleton serves as track for the long-range transport of subcellular organelles and of vesicular intermediates that mediate intracellular communication. The motility occurs on dynamic and polarized microtubules tracks, with their growing plus-end directed towards the cell periphery and stable minus-end anchored at the microtubule-organizing centre (MTOC). This intracellular microtubule-based transport relies on the activity of two classes of molecular motor proteins, namely kinesin and dynein. While there are several distinct kinesin proteins that mediate anterograde cellular transport (i.e. towards the plasma membrane), a single cytoplasmic dynein (hereafter referred to as dynein) regulates bulk of the retrograde cargo transport (i.e. towards the MTOC). Dynein is a large multi-subunit complex comprising two copies each of catalytic heavy chain (DHC), intermediate chain (IC), light intermediate chain (LIC), the light chain (LC) and accessory polypeptides (Roadblock and Tctex-1). Dynein associates with its multi-subunit activator; dynactin, and formation of the dynein-dynactin complex enhance the processivity of this retrograde motor4-7. The interaction between mammalian dynein and dynactin is strengthened by multiple co-factors termed as ‘activating adaptors’. The common feature among these dynein adaptors is the presence of long (>200 residues) coiled-coil domains1, 6. The activating adaptors link dynein and dynactin in a stable ternary configuration with microtubulebinding domains of both DHCs aligned and attached to the microtubules while possibly relieving the auto-inhibited state of dynactin and inducing superprocessive motility the motor complex1, 7, 8.

Multiple coiled-coil activating adaptors like Bicaudal D2 (BICD2), Spindly, HOOK3 and

Rab11/FIP3 are known to associate with dynein and regulate its activity, as well as link the motor to different cargoes, and hence, provide specificity towards cargo selection by the motor6, 9, 10.

This review focuses on the Hook proteins that are evolutionarily conserved coiled-coil

domain-containing proteins recently shown to act as activating adaptors for dynein. Discovery of Hook proteins is attributed to the peculiar hooked-bristle phenotype in Hook-deficient Drosophila melanogaster11. While a single Hook gene is present in lower eukaryotes including fungi, flies and worm; vertebrates contain two or more Hook paralogs with diverse functions and distinct subcellular localization12. Mammals, for instance, express three Hook paralogs namely HOOK1, HOOK2 and HOOK312, 13. In this review, we highlight recent advances in our understanding of Hook proteins, their role as dynein adaptors and their known cellular functions.


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Structure of Hook proteins: Hook proteins are conserved across evolution with an N-terminal hook domain

that

mediates

binding,

two

leucine-zipper-like

central

coiled-coil

dyneindomains

mediating homo-dimerization14 and highly divergent C-terminal region responsible

for

association12,

13, 15, 16

Hook

their

proteins

organelle

(Fig. 1A-B).

across

different

species share around 50% sequence similarity with their N-terminal Hook

domain

being

the

most

conserved. Initial report on Hook proteins

identified

them

proteins12,

microtubule-binding however,

as

subsequent

Figure 1: (A) Schematic representation of domain architecture of Hook proteins. The conserved residues present in the Hook

studies

domain for binding to the C-terminus of DLIC1 are shown (*) in

contradicted these earlier findings

the zoomed alignment below. The sequence alignment of the

and showed that Hook protein-

spindly motif in Hook proteins and other dynein adaptors is

microtubule interaction was not detectable in microtubule-pelleting assays15, 17.

Indeed, while the Hook

shown in the zoomed alignment. Starred positions indicate the conserved residues in both cases. The critical Phenylalanine in Spindly and BICD1 is indicated with an arrowhead. (B) Schematic representation showing Hook proteins in different

calponin

species share maximum and least similarity at their N- and C-

homology (CH) fold implicated in

terminal, respectively. (C) Assembly of dynein-dynactin

domain

contains

microtubule

the

association

microtubule-associated

of

proteins

complex by Hook proteins. The N-terminal Hook domain binds to the C-terminal of DLIC1, the coiled-coil runs along the ARP1 filament and the C-terminal binds to the cargo (not shown). Hook

(MAPs) like EB1, the specific

proteins form a stable ternary complex with dynein and dynactin,

residues required for interaction

and help stabilize the conformation of the dynein-dynactin

with microtubules are not conserved

complex, which is necessary for dynein processivity 1-3.


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Biochemistry

in mammalian Hook proteins17. Thus, it is likely that Hook proteins do not directly bind to the microtubules. In a recent study, the crystal structure of Hook domain of human HOOK3 was determined at 1.7 A° resolution using X-ray diffraction and molecular replacement with the NMR structure of N-terminus of mouse HOOK1 used as a template (PDB ID: 1WIX)8. The crystal structure revealed that in addition to the canonical seven-helix CH fold, HOOK3 contains an additional extended eighth helix. Sequence of this eighth helix is conserved across evolution and contains two solvent-exposed residues (Q147 and I154) that were shown to interact with the conserved residues in the C-terminal region of light intermediate chain (LIC) 1, a subunit of dynein8,

18

(Fig. 1A). Indeed, a recent crystal structure of the Hook domain of HOOK3 in

complex with the human LIC Helix-1 peptide (residues 433-458) has revealed a conformational change in this extended eighth helix of the Hook domain that exposes a conserved hydrophobic cleft for binding of the conserved LIC Helix-118. Notably, besides the Hook domain, two other modes of recognition of dynein LIC C-terminus by the activating adaptors has been proposed, namely, via a motif within the coiled coil region referred to as "CC1 box" (AAxxG) (such as in BICD2, BICD family-like cargo adapter 1 (BICDL1) and Spindly) or via a region containing a pair of EF-hand motifs (as in Rab11FIP3)1. The LIC Helix-1 also binds to the CC1-box containing dynein-dynactin activating adaptors, including, BICD2 and Spindly18. Downstream of the hook domain and between the two-consecutive coiled-coil regions, mammalian Hook paralogs contain a stretch of six amino acid residues, which are similar to the “spindly motif” (SLFAEV) first identified in the dynein adaptor Spindly, and is a site for interaction with the pointed-end complex of the dynactin complex19,

20.

Notably, Hook proteins (similar to many

other dynein adaptors) lack the phenylalanine residue in the spindly motif, which is required for interaction of Spindly with the dynactin pointed end complex20 (Fig. 1A). It would be important to determine the contribution of this spindly-like motif in Hook protein binding to the dyneindynactin complex, especially as p25 subunit of the dynactin pointed end complex is essential for Hook protein interaction with the dynein-dynactin complex15, 21. A recent structural analysis of full-length HOOK1 using rotatory shadowing electron microscopy has revealed that HOOK1 exist as a dimer with kinesin-like appearance where most particles displayed two globular domains at one end that were connected to a long thin rod with a pronounced kink followed by a thin stalk. The spindly motif present between the two coiled-coils


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is thought to form the kink, possibly serving as a hinge in the stalk that connects the two globules, 18. However, the importance of this kinesin-like configuration and the exact role of the spindly motif in Hook proteins will require further investigation. We next discuss the studies done in lower eukaryotes, which first revealed the role of Hook domain in dynein binding that was later found to be a conserved function of Hook paralogs in mammals as well. Evolutionary conserved function of Hook proteins as dynein adaptors: Earlier studies involving microtubule spin-down assays and immunofluorescence characterized Hook proteins as microtubule-binding proteins that promote association of subcellular organelles to the microtubules12, 13. The first evidence of interaction between the N-terminal region of Hook proteins and dynein was reported in C. elegans model system where the Hook homolog ZYG-12 was shown to recruit dynein onto the nuclear envelope through its association with dynein lightintermediate chain (DLI-1), albeit the study did not reveal whether there was a direct binding between ZYG-12 and DLI-122. This interaction is conserved across evolution as mammalian Hook paralog; HOOK3 also binds to C-terminal region of LIC1, forming a processive tripartite complex containing dynein, dynactin and HOOK38, 18. Importantly, studies in the fungal model organisms, Aspergillus nidulans and Ustilago maydis, first demonstrated the role of Hook proteins as linker for dynein-dependent organelle motility where the N-terminal region of the Hook protein was shown to associate with dynein while the C-terminal domain mediated recruitment to early endosomes, promoting retrograde transport of early endosomes in the fungal hyphae15, 16. In addition to engaging dynein, Ustilago Hook ortholog, Hok1, was shown to bind the anterograde motor protein kinesin-3 that likely creates a tug-of-war situation between the two opposing microtubule motors16. Further investigation is required to determine whether the tug-of war between kinesin-3 and dynein is due to competitive binding of both the motors to Hok1. Similar to the fungal Hooks, human HOOK1 and HOOK3 were subsequently shown to regulate dynein-dependent retrieval of Rab5-postive early endosomes from axons to the cell body in rat hippocampal neurons23. Notably, fungi and mammalian Hook proteins are not directly associated with the early endosomal membranes but are recruited to the early endosomes by binding to the Fused-Toes (FTS) and FTS-Hook Interacting Protein (FHIP) protein complex23,

24.

The

interaction of Hook proteins with FTS and FHIP, forming a FTS/Hook/FHIP (FHF) complex, was first identified for the mammalian Hooks and was later found to be conserved for the


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Biochemistry

Ustilago maydis Hook protein14, 16. Later studies have revealed that the FHIP subunit in fungal (Aspergillus) and mammalian FHF complex localizes to the early endosomes (likely via its direct binding to the early endosomal Rab protein) and recruits Hook protein to mediate dyneindependent early endosome motility23, 24. The exact function of FTS in this complex is not clear but it is required for the stability of the FHIP subunit, and, therefore, for the formation of the FHF complex 24. As Hook paralog in filamentous fungi were reported to mediate dynein-dependent early endosome motility; accordingly role of mammalian Hook proteins in promoting dynein-dynactin association and activating dynein motility was also investigated. Using the approach of in vitro biochemical reconstitution followed by single-molecule motility assays, these studies established the role of human HOOK3 and HOOK1 in activating dynein motility6,

8, 17.

The coiled-coil

region of HOOK3 was shown to be essential in strengthening the binding to dynein-dynactin and for the robust activation of dynein motility8. In the context of Hook association with dyneindynactin complex, it remains to be addressed whether mammalian Hook proteins also directly bind to other subunits of the dynein-dynactin complex. Indeed, previous studies have shown that p25, a pointed end complex subunit of the dynactin complex, is required for dynein-dynactin binding to HookA, Hook homolog in Aspergillus nidulans15,

21.

Recent studies on the three

dimensional structure of the dynein-dynactin-Hook complex have revealed new details about this tripartite complex. While the Hook domain binds dynein through LIC1, the coiled-coil region fits into the Arp1 groove of dynactin, possibly building a binding interface like another dynein adaptor, BICD22, 3. Interestingly, these studies also revealed that whereas activating adaptor like BICD2 is biased to recruit a single molecule of dynein per dynactin molecule, adaptors like HOOK3 and BICDR1 recruit two molecules of dynein per dynactin, resulting in a greater force production and robust motility of the active motor when in complex with HOOK32, 3 (Fig. 1C). Although we now have mechanistic insights into the regulation of dynein motility by Hook proteins, the information on the functional aspect of these interactions remain scanty and fragmented, warranting further exploration into the cellular functions of Hook proteins as dynein adaptors. Cellular roles of mammalian Hook paralogs:


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Most studies on the cellular functions of Hook proteins have been done in lower eukaryotes where a single Hook paralog is expressed and has been shown to regulate dynein recruitment and dynein-dynactin dependent cargo transport along the microtubule tracks

15, 16, 22.

In contrast,

mammals express three Hook paralogs namely, HOOK1, HOOK2 and HOOK3 with 85.8% overall similarity amongst each other. While the expression of HOOK1 is more restricted to certain tissues, HOOK2 and HOOK3 are ubiquitously expressed25, 26. Owing to their divergent C-terminus (~30% similar) (Fig. 1B), mammalian Hook paralogs localize to distinct cellular compartments (Fig. 2A-C) and perform diverse cellular functions, however, how their function as dynein adaptors fit into their cellular roles remains an open question.

Figure 2: Subcellular localization of Hook Proteins: (A) HeLa cells expressing GFP-Rab5 (early endosome marker) and co-stained for endogenous HOOK1 (stained in red with anti-HOOK1 antibody, gift from Dr. Helmut Krämer, University of Texas Southwestern Medical Center, Texas, USA). (B) HeLa cells stained for endogenous HOOK2 (stained in green with anti-HOOK2 antibody: ab154109; Abcam) and α-tubulin (microtubules) (stained in red with anti-α-tubulin antibody: T9026; Sigma). (C) HeLa cells stained for endogenous HOOK3 (stained in green with anti-HOOK3 antibody, gift from Dr. Helmut Krämer) and GM130 (Golgi marker) (Stained in red with anti-GM130 antibody: 610822; BD Biosciences). Scale bars, 10 µm.

HOOK1 was initially characterized as a microtubule-binding protein that associates with a microtubule-based structure known as “manchette” in spermatozoa and regulates maturation of spermatozoa head and tail. The defects in this process lead to decapacitation of sperm head from flagellum, thus affecting fertilization capacity of sperms27. Ubiquitously expressed HOOK3 localizes to the Golgi (Fig. 2C) and controls its perinuclear positioning and architecture12. HOOK3 also binds to the pericentriolar satellite protein PCM1 and regulates PCM assembly and neurogenesis in mouse neural progenitor cells as well as HOOK3 expression is required for the maintenance of neuronal progenitor pool28. In a pathological context, reduced expression of HOOK1 and HOOK3 was reported in brain tissues of patients with Alzheimer's disease. More importantly, HOOK3 depletion was reported to enhance β-amyloid production, suggesting a role


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Biochemistry

for Hook proteins in the clearance of toxic protein aggregates, possibly by regulating their endosomal transport

29.

Only a few studies thus far have directly analyzed the role of Hook

proteins in dynein-dependent cargo transport. For instance, it was recently shown that HOOK1 and HOOK3, in association with the FTS/FHIP protein complex, physically associate with Rab5 and promote retrograde transport of receptor-containing carriers from axon to the soma of rat hippocampal neurons23. Furthermore, HOOK1, but not HOOK3, was shown to act as a specific dynein effector for the retrograde transport of TrkB–brain-derived neurotrophic factor (BDNF)signaling endosomes in rat hippocampal neurons, suggesting a cargo-specific adaptor function for Hook proteins30. HOOK1, together with Rab22a also regulates the recycling of clathrinindependent endocytosed (CIE) cargo receptors, however whether this plus-end transport actually involves HOOK1 interaction with a microtubule-based motor remains unclear31. While HOOK1 and HOOK3 have mainly been studied in the context of membranous organelles, studies on HOOK2 have primarily focused on its localization at the centrosome (Fig. 2B), a non-membrane subcellular organelle. HOOK2 regulates the formation of aggresome, a structure formed at the centrosome by dynein-dependent transport of misfolded proteins that are eventually degraded by the ubiquitin-proteasome system32. HOOK2 also associates with multiple proteins at the centrosome like PCM1, Centriolin and CENP-F through its C-terminus and regulates microtubule organization and nucleation at the centrosome13, 33. In ciliated epithelial cells, HOOK2 recruits Rab8A to the ciliary base and regulate the formation of primary cilia that are microtubule-based structures protruding from the cell surface and perform mechano-sensory transduction function34, 35. Further HOOK2 associates with polarity complex protein Par6α and regulates centrosome positioning in migrating cells, a key player in regulating cell migration36. As Par6α regulates the transport of pericentrosomal matrix proteins to centrosomes in a dyneindependent manner37, 38, the interaction between HOOK2 and Par6α might have significance in centrosome assembly and maturation processes. Although most of these cellular functions ascribed to HOOK2 are known to be dependent on dynein activity, the role of HOOK2 in regulating dynein motility has not been reported. Multiple studies have implicated the role of HOOK2 in centrosomal functions like ciliogenesis and organization of microtubule cytoskeleton13, 33, 35. As centrosomes become spindle poles and perform a pivotal role during the cell cycle, a process tightly regulated by dynein at multiple steps39-48, it would be interesting to explore the role of HOOK2 in regulating dynein function during the cell cycle. We have recently


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found that HOOK2 regulates dynein-dynactin association during specific stages of the cell cycle and HOOK2 function is required for centrosome anchoring at the nuclear envelope, chromosome alignment and spindle positioning. Interestingly, we also found that HOOK2 mediates dynactindependent targeting of the centralspindlin complex at the midzone required for the formation and ingression of the cleavage furrow during cytokinesis49. Mammalian Hook proteins also form homodimers and heterodimers and assemble in large complexes with their binding partners FTS and FHIP14. However, it remains to be investigated whether heterodimers of the Hook proteins exist at endogenous levels and how a Hook heterodimer complex might regulate dynein localization and function. Concluding remarks and open questions: Hook proteins bind the retrograde motor dynein and enhance its motility by stabilizing interaction with, and possibly modulating dynactin conformation, converting dynein-dynactin complex into a super-processive motor. Hook proteins regulate multiple cellular processes that are dependent on dynein activity; however, our current knowledge of how the dynein adaptor function of mammalian Hook proteins is required for their ascribed cellular functions needs further exploration. Dynein associates with multiple adaptors to regulate numerous intracellular processes. How dynein association with adaptors having a similar expression pattern is spatiotemporally regulated, remains unexplored. This question is more relevant in case of mammalian Hook proteins, as they are highly similar in sequence and will likely have a similar interface for binding to dynein-dynactin complex. It will be important to explore whether the mammalian Hook proteins compete for dynein association and whether they are differentially expressed or post-translationally modified to avoid a possible competition. Future studies using advanced

high-resolution

microscopy,

and

in

vitro

assays

combined

with

RNA

interference/CRISPR-based gene knockout approaches are required to bridge the existing gap between the mechanism of Hook-mediated dynein regulation and their subcellular functions.

References:


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Biochemistry

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