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Walking Proteins Need To Rock And Roll, New Study Finds

Date:
July 2, 2001
Source:
Stanford University
Summary:
Unlike a congested city commute, cellular traffic is efficient and highly regulated - thanks in part to a group of proteins known as motor molecules that use microtubules to haul vital cargo through the cell. A study featured on the cover of the June issue of the journal Nature Structural Biology adds an important piece to the puzzle.

The inside of a living cell has been compared to a train station at rush hour, with enzymes, chromosomes and other internal components constantly being shuttled along tiny fibrous tracks called microtubules.

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Unlike a congested city commute, cellular traffic is efficient and highly regulated - thanks in part to a group of proteins known as motor molecules that use microtubules to haul vital cargo through the cell.

In 1985, biologists identified a molecular motor called kinesin that has turned out to be responsible for a variety of critical hauling jobs, such as separating chromosomes during cell division and ferrying neurotransmitters inside nerve cells.

Studies have shown that while one end of a kinesin molecule holds onto its cargo, the other end uses a remarkable two-headed structure to grab the microtubule and pull the cargo forward - a process called "kinesin walking" (see web animations at http://www.scripps.edu/milligan/projects and http://mc11.mcri.ac.uk/wrongtrousers.html).

Researchers are interested in unraveling the mystery of how kinesins walk along microtubules, and whether defective walking contributes to a variety of human ailments - including spontaneous abortion, tumor growth, infertility and neurodegenerative diseases such as Alzheimer's and retinitis pigmentosa.

A study featured on the cover of the June issue of the journal Nature Structural Biology adds an important piece to the puzzle.

"There is a lot of interest in kinesin and how it works as a motor," says Stanford chemistry Professor W. E. Moerner, co-author of the June study. "Measurements have been made of the forces kinesin produces as it walks, but we'd like to know how it is oriented when it moves as well."

HEAD OVER HEAD

Kinesin walking is controlled by the breakdown of ATP - a molecule that provides energy for all cellular activity in the body. From different lines of evidence, scientists have proposed a model in which chemical changes in ATP cause kinesin to alternately bind each of its two heads to a microtubule. This "head-over-head" leapfrogging action propels kinesin forward, much as a child moves along a horizontal rope by alternately placing one hand in front of the other.

Unlike kids on a playground, kinesin activity is measured in nanometers. One nanometer is one-billionth of a meter - or about 50,000 times smaller than the width of a human hair.

Stanford biophysicist Steven Block recently discovered that kinesin heads walk in steps that are exactly 8 nanometers apart. But X-ray crystal analysis of kinesin shows that its two heads are separated by only 5 nanometers of space. So where do the additional 3 nanometers come from that are necessary to complete an 8-nanometer step?

To solve the puzzle, Moerner and his colleagues used a novel technique that allowed them to observe the movement of a single kinesin molecule - an object only one ten-millionth of an inch long.

"We use a fluorescing label molecule - or fluorophore - to measure orientation," says Moerner. "The fluorophore, which is bound to the kinesin head with two chemical bonds, absorbs and emits light in a special pattern as the head turns."

By measuring different levels of brightness and darkness, Moerner and his co-workers were able to determine the orientation of the head in relation to a microtubule in the presence of the different chemical forms of ATP.

The results were surprising.

"If the head were rigidly attached to a microtubule, we'd expect to see a light-dark-light-dark fluorescent pattern," notes Moerner. "But what if the head is rocking around? Then all of the images would have equal brightness. That's what we observed: With one of the forms of ATP, kinesin rocks!"

WOBBLING

Moerner and his team offer one possible explanation of how a single, 8-nanometer step of kinesin might occur:

First, a molecule of ATP binds with Head 1, causing the head to become firmly attached to the microtubule. Head 2 then leapfrogs over Head 1 by the maximum allowable distance of 5 nanometers, but instead of becoming rigidly fixed, Head 2 rocks back and forth on the surface of the microtubule. The breakdown of ATP then causes Head 1 to wobble uncontrollably, giving Head 2 just enough slack to roll forward an additional 3 nanometers. At that point, Head 2 becomes firmly bound to the microtubule, while Head 1 leapfrogs another step forward.

Each 8-nanometer step takes only about 10 milliseconds to complete, says Moerner, noting that the alternating rigid and wobbly states of the two heads could allow kinesin to complete a typical 1,000-nanometer walk in a few seconds before separating from the microtubule.

He points out that some kinesins work in teams in order to transport their cargo very long distances.

"There are some nerve cells that extend from the spine to the foot," Moerner observes. "It takes one or two days for kinesins to carry vesicle containers loaded with neurotransmitters from end to end via microtubules embedded in the nerve."

He compares the movement to a relay race in which kinesin molecules hand off vesicles to one another all the way down the nerve axon, thus guaranteeing a constant supply of neurotransmitters at the synapse located in the foot.

"We don't know all of the implications of our findings," Moerner points out. "In the future, we hope to observe the orientation of kinesin as it takes multiple steps. That's one of the virtues of single-molecule measurements: You can look at biological systems in a native environment, and thus see movement rather than a static structure."

In addition to Moerner, the other co-authors of the June Nature Structural Biology study are Hernando Sosa of the Albert Einstein College of Medicine; Erwin J. G. Peterman, a former chemistry postdoctoral fellow at Stanford now at the Free University in the Netherlands; and Lawrence S. B. Goldstein of the University of California-San Diego and the Howard Hughes Medical Institute.

Relevant Web URLs:

http://www.stanford.edu/group/moerner

http://www.blocks.fhcrc.org/~kinesin/

http://mc11.mcri.ac.uk/wrongtrousers.html

http://www.scripps.edu/milligan/projects


Story Source:

The above story is based on materials provided by Stanford University. Note: Materials may be edited for content and length.


Cite This Page:

Stanford University. "Walking Proteins Need To Rock And Roll, New Study Finds." ScienceDaily. ScienceDaily, 2 July 2001. <www.sciencedaily.com/releases/2001/07/010702090028.htm>.
Stanford University. (2001, July 2). Walking Proteins Need To Rock And Roll, New Study Finds. ScienceDaily. Retrieved November 28, 2014 from www.sciencedaily.com/releases/2001/07/010702090028.htm
Stanford University. "Walking Proteins Need To Rock And Roll, New Study Finds." ScienceDaily. www.sciencedaily.com/releases/2001/07/010702090028.htm (accessed November 28, 2014).

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