Research Achievements

October 18, 2021 

First evidence of microtubules' mechanosensitive behavior

Direct evidence that microtubules function as mechanosensors and regulate the intracellular transport of molecules has been reported, leading to new possibilities in the fields of biomechanics, medicine, and biosensors.

 

 

Joint press release by Hokkaido University; the National Institutes of Natural Sciences; Research Center for Advanced Science and Technology (RCAST), The University of Tokyo; Yokohama City University; and Nagoya University.

 

 

Inside cells, microtubules not only serve as a component of the cytoskeleton (cell skeleton) but also play a role in intracellular transport. In intracellular transport, microtubules act as rails for motor proteins such as kinesin and dynein. Microtubules, the most rigid cytoskeletal component, are constantly subjected to various mechanical stresses such as compression, tension, and bending during cellular activities. It has been hypothesized that microtubules also function as mechanosensors that convert mechanical information into biochemical information.

 

A research team led by Associate Professor Akira Kakugo of Hokkaido University has provided direct evidence that microtubules function as mechanosensors that regulate intracellular transport. The findings were published in the journal Science Advances. The team included Dr. Syeda Rubaiya Nasrin, Seiji Nishikawa, Dr. Arif Md. Rashedul Kabir and Professor Kazuki Sada of Hokkaido University; Dr. Christian Ganser of the National Institutes of Natural Sciences; Associate Professor Takefumi Yamashita of Research Center for Advanced Science and Technology (RCAST), The University of Tokyo; Professor Mitsunori Ikeguchi of Yokohama City University; Professor Takayuki Uchihashi of Nagoya University; and Professor Henry Hess of Columbia University.

 

Recent studies have shown that mechanical stress has a significant effect on cell differentiation, development, and disease. Some studies have suggested that microtubules, which are the most rigid cytoskeleton and play an important role in cell morphogenesis and intracellular material transport, may also function as mechanosensors; however, no direct evidence has been obtained to support such a speculation.

 

 

The high-speed atomic force microscope used in the study

(Photo: Akira Kakugo)

 

 

The team carried out experiments with microtubules in a cell free system. They found that kinesin movement is slowed down when the microtubule is bent. Using high-speed atomic force microscopy, which allows for the observation of dynamic processes at the atomic level, they confirmed that this phenomenon occurs even without cavities or cracks in the microtubule structure, which were thought to be the main reason behind the slowing. Analysis of the kinesin binding affinity showed that bent microtubules appear stickier to kinesin compared to unbent microtubules. From all-atom molecular dynamics simulations, it was found that the mechanism of such slowing down involves the enhanced interaction energy of kinesin and deformed microtubule structural units.

 

 

 

Microtubule, a cytoskeletal filament, may function as a mechano-sensor to regulate intracellular transport by its motor protein, kinesin. Tension, flexure, or compression in the microtubule filament slowed down the kinesin movement along the microtubule due to increased intermolecular interaction, as proved by the molecular dynamics simulation

(Syeda Rubaiya Nasrin, Christian Ganser, et al. Science Advances. October 13, 2021).

 

 

 

The results of this research have implications in the fields of biomechanics and mechanobiology, that study the mechanical environment in and around cells; in research on neurological diseases caused by impeded axonal cargo transport; and for the development of mechanical sensors by biomolecular proteins.

 

 

 

From the left: Syeda Rubaiya Nasrin and Akira Kakugo, Hokkaido University; Christian Ganser, National Institutes of Natural Sciences; Takefumi Yamashita, RCAST, The University of Tokyo;  Mitsunori Ikeguchi, Yokohama City University; Takayuki Uchihashi, Nagoya University; and Henry Hess, Columbia University

(Photos: Syeda Rubaiya Nasrin, Akira Kakugo, Christian Ganser, Takefumi Yamashita, Mitsunori Ikeguchi, Takayuki Uchihashi, Henry Hess).

 

 

 

Original Article:

Syeda Rubaiya Nasrin, Christian Ganser, et al. Deformation of microtubules regulates translocation dynamics of kinesin. Science Advances. October 13, 2021.

DOI: 10.1126/sciadv.abf2211

 

Funding:

This study was supported by the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research on Innovative Areas "Molecular Robotics" KAKENHI (JP24104004), JSPS Molecular Engine grant (18H05423, 18H05426, 19H05389), Grants for Scientific Research (A; 18H03673, 21H04434), JSPS Grant-in-Aid for Challenging Research (Exploratory; 21K19877), Program for Promoting Researches on the Supercomputer Fugaku grant (JPMXP1020200201) and computational resources of the Fugaku computer and TSUBAME computer (hp200129, hp210172), Grant for Scientific Research (B; 18H01837); and the National Science Foundation (NSF), USA (1662329).

 

Contacts:

Associate Professor Akira Kakugo

Faculty of Science

Hokkaido University

Tel: +81-11-706-3474

Email: kakugo[at]sci.hokudai.ac.jp

 

Associate Professor Toshifumi Yamashita

Research Center for Advanced Science and Technology (RCAST)

The University of Tokyo

Tel: +81-3-5452-5453

Email: yamashita[at]lsbm.org

 

Professor Mitsunori Ikeguchi

Graduate School of Biomedical Sciences

Yokohama City University

Tel: +81-45-508-7232

Email: ike[at]yokohama-cu.ac.jp

 

Professor Takayuki Uchihashi

Graduate School of Science

Nagoya University

Tel: +81-52-789-2885

Email: uchihast[at]d.phys.nagoya-u.ac.jp

 

Sohail Keegan Pinto (International Public Relations Specialist)

Public Relations Division

Hokkaido University

Tel: +81-11-706-2185

Skype: hokudai.pr1

Email: en-press[at]general.hokudai.ac.jp

 

Collaborative Research Promotion Office

Exploratory Research Center on Life and Living Systems (ExCELLS)

National Institutes of Natural Sciences

Tel: +81-564-59-5201

Email: press[at]excells.orion.ac.jp

 

Research Center for Advanced Science and Technology (RCAST)

The University of Tokyo

Tel: +81-3-5452-5424

Email: press[at]rcast.u-tokyo.ac.jp

 

Public Relations Section

Planning and General Affairs Department

Yokohama City University

Tel: +81-45-787-2414

Email: koho[at]yokohama-cu.ac.jp

 

Public Relations Office

General Affairs Division

Administration Department
Nagoya University

Tel: +81-52-789-3058

Email: kouho-en[at]adm.nagoya-u.ac.jp

 

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