Interplay between microtubule dynamics and intracellular organization

Forges, Hélène de; Bouissou, Anaïs; Perez, Franck

doi:10.1016/j.biocel.2011.11.009

Cited by 205 publications

(160 citation statements)

References 135 publications

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“…These filamentous polymer structures are highly dynamic and undergo constant and rapid reorganization during cellular life cycle. The microtubule system plays a crucial role in brain physiology, as it is involved in an enormous number of cellular events including cell differentiation and pathological inclusion formation [1,2]. These various functions of microtubules are achieved by their decoration with proteins/enzymes that exert specific effects on the dynamics and the organization of the cytoskeleton resulting in distinct functions with moonlighting features [3].…”

Section: Introductionmentioning

confidence: 99%

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Szénási¹,

Oláh²,

Szabó³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The hallmarks of Parkinson's disease and other synucleinopathies, Tubulin Polymerization Promoting Protein (TPPP/p25) and α-synuclein (SYN) have two key features: they are disordered and co-enriched/co-localized in brain inclusions. These Neomorphic Moonlighting Proteins display both physiological and pathological functions due to their interactions with distinct partners. To achieve the selective targeting of the pathological TPPP/p25-SYN but not the physiological TPPP/ p25-tubulin complex, their interfaces were identified as a specific innovative strategy for the development of anti-Parkinson drugs. Therefore, the interactions of TPPP/p25 with tubulin and SYN were characterized which suggested the involvements of the 178-187 aa and 147-156 aa segments in the complexation of TPPP/p25 with tubulin and SYN, respectively. However, various truncated and deletion mutants reduced but did not abolish the interactions except one mutant; in addition synthetized fragments corresponding to the potential binding segments of TPPP/p25 failed to interact with SYN. In fact, the studies of the multiple interactions at molecular and cellular levels revealed the high conformational plasticity, chameleon feature, of TPPP/p25 that ensures exceptional functional resilience; the lack of previously identified binding segments could be replaced by other segments. The experimental results are underlined by distinct bioinformatics tools. All these data revealed that although targeting chameleon proteins is a challenging task, nevertheless, the validation of a drug target can be achieved by identifying the interface of complexes of the partner proteins existing at the given pathological conditions.

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Section: Introductionmentioning

confidence: 99%

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Szénási¹,

Oláh²,

Szabó³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…single-molecule FRET | intrinsically disordered proteins | microtubuleassociated protein | tauopathies | Alzheimer's disease M icrotubules play an important role in a host of critical cellular processes, including positioning of organelles, maintaining cell shape, axonal transport, and cell division (1)(2)(3). Their constituent subunits, α/β-tubulin heterodimers, polymerize head to tail to form linear protofilaments that subsequently associate laterally into microtubules.…”

mentioning

confidence: 99%

A functional role for intrinsic disorder in the tau-tubulin complex

Melo

Coraor

Alpha-Cobb

et al. 2016

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

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Tau is an intrinsically disordered protein with an important role in maintaining the dynamic instability of neuronal microtubules. Despite intensive study, a detailed understanding of the functional mechanism of tau is lacking. Here, we address this deficiency by using intramolecular single-molecule Förster Resonance Energy Transfer (smFRET) to characterize the conformational ensemble of tau bound to soluble tubulin heterodimers.Tau adopts an open conformation on binding tubulin, in which the long-range contacts between both termini and the microtubule binding region that characterize its compact solution structure are diminished. Moreover, the individual repeats within the microtubule binding region that directly interface with tubulin expand to accommodate tubulin binding, despite a lack of extension in the overall dimensions of this region. These results suggest that the disordered nature of tau provides the significant flexibility required to allow for local changes in conformation while preserving global features. The tubulin-associated conformational ensemble is distinct from its aggregation-prone one, highlighting differences between functional and dysfunctional states of tau. Using constraints derived from our measurements, we construct a model of tubulin-bound tau, which draws attention to the importance of the role of tau's conformational plasticity in function.single-molecule FRET | intrinsically disordered proteins | microtubuleassociated protein | tauopathies | Alzheimer's disease

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“…Furthermore, in a previous work we demonstrated that AT3 tightly binds tubulin dimers, the constituents of microtubules (Mazzucchelli et al, 2009). Microtubules are essential components of the cytoskeleton that play a major role in many cellular functions, including the retrograde transport of misfolded proteins to the aggresomes at MTOC (de Forges et al, 2012).…”

Section: Introductionmentioning

confidence: 89%

Interactions of ataxin-3 with its molecular partners in the protein machinery that sorts protein aggregates to the aggresome

Bonanomi

Mazzucchelli

D’Urzo

et al. 2014

The International Journal of Biochemistry & Cell Biology

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a b s t r a c tAtaxin-3 (AT3) is the protein that triggers the inherited neurodegenerative disorder spinocerebellar ataxia type 3 when its polyglutamine (polyQ) stretch close to the C-terminus exceeds a critical length. AT3 consists of the N-terminal globular Josephin domain (JD) and the C-terminal disordered one. It cleaves isopeptide bonds between ubiquitin monomers, an event involved in protein quality control mechanisms. AT3 has been implicated in the pathway that sorts aggregated protein to aggresomes via microtubules, in which dynein and histone deacetylase 6 (HDAC6) also seem to be involved. By taking advantage of small angle X-ray scattering (SAXS) and surface plasmon resonance (SPR), we have investigated the interaction of AT3 with tubulin and HDAC6. Based on SAXS results, the AT3 oligomer, consisting of 6-7 subunits, tightly binds to the tubulin hexameric oligomer in a "parallel" fashion. By SPR analysis we have demonstrated that AT3 binds to tubulin dimer with a 50 nM affinity. Binding fits with a Langmuir 1:1 model and involves a single binding interface. Nevertheless, the interaction surface consists of three distinct, discontinuous tubulin-binding regions (TBR), one located in the JD, and the two others in the disordered domain, upstream and downstream of the polyQ stretch. In the absence of any of the three TBRs, the affinity is drastically reduced. By SPR we have also provided the first evidence of direct binding of AT3 to HDAC6, with affinity in the range 0.1-1 M. These results shed light on the interactions among the components of the transport machinery that sorts aggregate protein to the aggresome, and pave the way to in vivo studies aimed at further clarifying their roles.

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Interplay between microtubule dynamics and intracellular organization

Cited by 205 publications

References 135 publications

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

A functional role for intrinsic disorder in the tau-tubulin complex

Interactions of ataxin-3 with its molecular partners in the protein machinery that sorts protein aggregates to the aggresome

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