scholarly journals Kinesin-binding protein remodels the kinesin motor to prevent microtubule binding

2021 ◽  
Vol 7 (47) ◽  
Author(s):  
April L. Solon ◽  
Zhenyu Tan ◽  
Katherine L. Schutt ◽  
Lauren Jepsen ◽  
Sarah E. Haynes ◽  
...  
Keyword(s):  
Binding Protein ◽  
Kinesin Motor ◽  
Microtubule Binding

scholarly journals Kinesin-binding protein remodels the kinesin motor to prevent microtubule-binding

2021 ◽  
Author(s):  
April L Solon ◽  
Zhenyu Tan ◽  
Katherine L Schutt ◽  
Lauren Jepsen ◽  
Sarah E Haynes ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Binding Protein ◽  
Structural Element ◽  
Kinesin Motor ◽  
Microtubule Binding ◽  
Structural Mechanism ◽  
Binding Interface ◽  
Α Helix ◽  
Motor Head

Kinesins are tightly regulated in space and time to control their activation in the absence of cargo-binding. Kinesin-binding protein (KIFBP) was recently discovered to bind the catalytic motor heads of 8 of the 45 known kinesin superfamily members and inhibit binding to microtubules. In humans, mutation of KIFBP gives rise to Goldberg-Shprintzen syndrome (GOSHS), but the kinesin(s) that is misregulated to produce clinical features of the disease is not known. Understanding the structural mechanism by which KIFBP selects its kinesin binding partners will be key to unlocking this knowledge. Using a combination of cryo-electron microscopy and crosslinking mass spectrometry, we determined structures of KIFBP alone and in complex with two mitotic kinesins, revealing regions of KIFBP that participate in complex formation. KIFBP adopts an alpha-helical solenoid structure composed of TPR repeats. We find that KIFBP uses a 2-pronged mechanism to remodel kinesin motors and block microtubule-binding. First, KIFBP engages the microtubule-binding interface and sterically blocks interaction with microtubules. Second, KIFBP induces allosteric conformational changes to the kinesin motor head that displace a key structural element in the kinesin motor head (α-helix 4) required for microtubule binding. We identified two regions of KIFBP necessary for in vitro kinesin-binding as well as cellular regulation during mitosis. Taken together, this work establishes the mechanism of kinesin inhibition by KIFBP and provides the first example of motor domain remodeling as a means to abrogate kinesin activity.

scholarly journals HkRP3 Is a Microtubule-Binding Protein Regulating Lytic Granule Clustering and NK Cell Killing

2015 ◽  
Vol 194 (8) ◽  
pp. 3984-3996 ◽  
Author(s):  
Hyoungjun Ham ◽  
Walter Huynh ◽  
Renee A. Schoon ◽  
Ronald D. Vale ◽  
Daniel D. Billadeau
Keyword(s):  
Nk Cell ◽  
Binding Protein ◽  
Cell Killing ◽  
Microtubule Binding ◽  
Lytic Granule

scholarly journals Interaction between the flagellar pocket collar and the hook complex via a novel microtubule-binding protein in Trypanosoma brucei

2017 ◽  
Vol 13 (11) ◽  
pp. e1006710 ◽  
Author(s):  
Anna Albisetti ◽  
Célia Florimond ◽  
Nicolas Landrein ◽  
Keni Vidilaseris ◽  
Marie Eggenspieler ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Binding Protein ◽  
Flagellar Pocket ◽  
Microtubule Binding

scholarly journals The mechanism of kinesin inhibition by kinesin-binding protein

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Joseph Atherton ◽  
Jessica JA Hummel ◽  
Natacha Olieric ◽  
Julia Locke ◽  
Alejandro Peña ◽  
...  
Keyword(s):  
Cell Function ◽  
Binding Protein ◽  
Eukaryotic Cell ◽  
Motor Domain ◽  
Tetratricopeptide Repeat ◽  
Kinesin Motor ◽  
Temporal Regulation ◽  
Cryo Electron Microscopy ◽  
Local Environments ◽  
Binding Surface

Subcellular compartmentalisation is necessary for eukaryotic cell function. Spatial and temporal regulation of kinesin activity is essential for building these local environments via control of intracellular cargo distribution. Kinesin-binding protein (KBP) interacts with a subset of kinesins via their motor domains, inhibits their microtubule (MT) attachment, and blocks their cellular function. However, its mechanisms of inhibition and selectivity have been unclear. Here we use cryo-electron microscopy to reveal the structure of KBP and of a KBP–kinesin motor domain complex. KBP is a tetratricopeptide repeat-containing, right-handed α-solenoid that sequesters the kinesin motor domain’s tubulin-binding surface, structurally distorting the motor domain and sterically blocking its MT attachment. KBP uses its α-solenoid concave face and edge loops to bind the kinesin motor domain, and selected structure-guided mutations disrupt KBP inhibition of kinesin transport in cells. The KBP-interacting motor domain surface contains motifs exclusively conserved in KBP-interacting kinesins, suggesting a basis for kinesin selectivity.

Smuggle tau through a secret(ory) pathway

2021 ◽  
Vol 478 (14) ◽  
pp. 2921-2925
Author(s):  
Hao Xu (徐昊)
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Recent Work ◽  
Molecular Mechanisms ◽  
Binding Protein ◽  
Nerve Cells ◽  
Transmembrane Domains ◽  
Tau Pathology ◽  
Microtubule Binding

Secretion of misfolded tau, a microtubule-binding protein enriched in nerve cells, is linked to the progression of tau pathology. However, the molecular mechanisms underlying tau secretion are poorly understood. Recent work by Lee et al. [Biochemical J. (2021) 478: 1471–1484] demonstrated that the transmembrane domains of syntaxin6 and syntaxin8 could be exploited for tau release, setting a stage for testing a novel hypothesis that has profound implications in tauopathies (e.g. Alzheimer's disease, FTDP-17, and CBD/PSP) and other related neurodegenerative diseases. The present commentary highlights the importance and limitations of the study, and discusses opportunities and directions for future investigations.

Inscuteable-dependent apical localization of the microtubule-binding protein Cornetto suggests a role in asymmetric cell division

2001 ◽  
Vol 114 (20) ◽  
pp. 3655-3662 ◽  
Author(s):  
Silvia Bulgheresi ◽  
Elke Kleiner ◽  
Juergen A. Knoblich
Keyword(s):  
Cell Fate ◽  
Mitotic Spindle ◽  
Binding Protein ◽  
Protein Localization ◽  
Apical Cell ◽  
Coiled Coil ◽  
Cell Cortex ◽  
Dependent Manner ◽  
Genetic Redundancy ◽  
Microtubule Binding

Drosophila neuroblasts divide asymmetrically along the apical-basal axis. The Inscuteable protein localizes to the apical cell cortex in neuroblasts from interphase to metaphase, but disappears in anaphase. Inscuteable is required for correct spindle orientation and for asymmetric localization of cell fate determinants to the opposite (basal) cell cortex. Here, we show that Inscuteable also directs asymmetric protein localization to the apical cell cortex during later stages of mitosis. In a two-hybrid screen for Inscuteable-binding proteins, we have identified the coiled-coil protein Cornetto, which shows a highly unusual subcellular distribution in neuroblasts. Although the protein is uniformly distributed in the cytoplasm during metaphase, it concentrates apically in anaphase and forms an apical crescent during telophase in an inscuteable-dependent manner. Upon overexpression, Cornetto localizes to astral microtubules and microtubule spin-down experiments demonstrate that Cornetto is a microtubule-binding protein. After disruption of the actin cytoskeleton, Cornetto localizes with microtubules throughout the cell cycle and decorates the mitotic spindle during metaphase. Our results reveal a novel pattern of asymmetric protein localization in Drosophila neuroblasts and are consistent with a function of Cornetto in anchoring the mitotic spindle during late phases of mitosis, even though our cornetto mutant analysis suggests that this function might be obscured by genetic redundancy.

CHARACTERISATION OF THE TRANSLATIONALLY REGULATED, MICROTUBULE BINDING PROTEIN P23

1996 ◽  
Vol 24 (4) ◽  
pp. 516S-516S
Author(s):  
Yannick Gachet ◽  
Melanie Lee ◽  
Birgit Sawitzki ◽  
Terry Poulton ◽  
Ulrich-Axel Bommer
Keyword(s):  
Binding Protein ◽  
Microtubule Binding

scholarly journals Bim1p/Yeb1p Mediates the Kar9p-dependent Cortical Attachment of Cytoplasmic Microtubules

2000 ◽  
Vol 11 (9) ◽  
pp. 2949-2959 ◽  
Author(s):  
Rita K. Miller ◽  
Soo-Chen Cheng ◽  
Mark D. Rose
Keyword(s):  
Fluorescent Protein ◽  
Binding Protein ◽  
Spindle Pole Body ◽  
Attachment Site ◽  
Spindle Pole ◽  
Cell Cortex ◽  
Microtubule Binding ◽  
Pole Body ◽  
Cytoplasmic Microtubules ◽  
Two Hybrid

In Saccharomyces cerevisiae, positioning of the mitotic spindle depends on the interaction of cytoplasmic microtubules with the cell cortex. In this process, cortical Kar9p in the bud acts as a link between the actin and microtubule cytoskeletons. To identify Kar9p-interacting proteins, a two-hybrid screen was conducted with the use of full-length Kar9p as bait, and three genes were identified: BIM1, STU2, andKAR9 itself. STU2 encodes a component of the spindle pole body. Bim1p is the yeast homologue of the human microtubule-binding protein EB1, which is a binding partner to the adenomatous polyposis coli protein involved in colon cancer. Eighty-nine amino acids within the third quarter of Bim1p was sufficient to confer interaction with Kar9p. The two-hybrid interactions were confirmed with the use of coimmunoprecipitation experiments. Genetic analysis placed Bim1p in the Kar9p pathway for nuclear migration. Bim1p was not required for Kar9p's cortical or spindle pole body localization. However, deletion ofBIM1 eliminated Kar9p localization along cytoplasmic microtubules. Furthermore, in the bim1 mutants, the cytoplasmic microtubules no longer intersected the cortical dot of Green Fluorescent Protein–Kar9p. These experiments demonstrate that the interaction of cytoplasmic microtubules with the Kar9p cortical attachment site requires the microtubule-binding protein Bim1p.

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