Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Keeping Cells Youthful: How Telomere-building Proteins Get Drawn Into the Fold

25.08.2008
It may take just one or two proteins to polish off a simple cellular task, but life-or-death matters, such as caring for the ends of chromosomes known as telomeres, require interacting crews of proteins, all with a common goal but each with a specialized task.

Researchers at the Salk Institute for Biological Studies led by Vicki Lundblad, Ph.D., a Professor in the Molecular and Cell Biology Laboratory, have discovered that a protein that helps elongate chromosome ends—and hence saves cells from premature growth arrest—likely recognizes where to report to work through a common fold. Those findings are reported ahead of print in the August 24 online edition of Nature Structure and Molecular Biology.

“Our studies have predicted a specific 3-dimensional shape displayed by a key protein that interacts with telomeres,” said Lundblad, explaining that analysis of this protein, called Est3, had been up to now particularly problematic. “This prediction has now provided us with a crucial tool that has propelled forward our studies of this protein.”

When cells divide, telomeres – the tails of repetitive DNA that extend from the ends of each chromosome – become progressively shorter. Telomeres function like cellular clocks: as they become critically stubby cells are no longer capable of dividing and undergo growth arrest termed cellular “senescence”. Fortunately, over the course of a cell’s lifetime, an enzyme complex known as telomerase works to restore telomeres to a more youthful length after each cell division.

Although the precise structure of human telomerase is not yet known, Lundblad had defined its budding yeast equivalent as containing three Est proteins complexed to an RNA ribbon: Est2 and the RNA do the heavy catalytic lifting in terms of telomere-reconstruction, while Est1 and Est3 orchestrate the process. But just how the two proteins ensured that things run smoothly was still unclear.

An earlier study in Lundblad’s group already answered this question for Est1: they showed that Est drags the telomerase complex to telomeres, an activity that is required to keep yeast cells continuously dividing. “Without Est1, telomerase cannot get to the ends of chromosomes, and thus telomeres shorten,” explained Lundblad.

In the current study Lundblad and co-first authors post-doctoral researcher Jaesung Lee, Ph.D., and graduate student Edward Mandell turned their attention to Est3 by first examining its computer-generated three-dimensional structure. They found that, like several other telomeric proteins, Est3 exhibited an architectural element known as an “OB” fold. Using computer models to scrutinize the fold surface, the group predicted that specific amino acids on one face of the fold might be required for interaction with the telomerase complex.

Laborious benchwork confirmed their predictions: the group biochemically inactivated each candidate amino acid separately, put each of those mutant proteins back into yeast cells, and then monitored whether that manipulation had any effect on telomere length or cell survival.

Their exhaustive analysis proved highly fruitful in terms of telomerase regulation: inactivation of a handful of suspect amino acids on one side of the surface of the protein produced shorter telomeres, showing that telomerase was now severely impaired.

Alterations in one cluster of amino acids lead to failure of Est3 to interact with its other Est protein partners. Disrupting a second set of amino acids leaves the telomerase complex intact, but with an inactive Est3 protein. Addressing what makes Est3 inactive is the subject of ongoing investigation.

“The recent increase in the ability to predict protein structure is now permitting detailed analysis of many proteins, including proteins like Est3, whose function had been mysterious,” says Lundblad.

An unanticipated but highly intriguing finding came from comparison of Est3 structure to that of other proteins. The group found that Est3 highly resembles a mammalian telomere-associated protein called TPP1. “This is surprising because TPP1 is not a subunit of the telomerase complex,” explained Lundblad, noting that instead TPP1’s job is to bind to and shelter telomeres from cellular repair enzymes that might mistake shaggy chromosome ends for damaged DNA — not to regulate their construction.

Factors that regulate telomerase activity are a very hot topic in biomedicine: sluggish telomerase activity promotes premature cell death and may underlie diseases of aging via telomere shortening, while hyperactive telomerase could promote uncontrolled cell division and cellular immortality associated with cancer.

The common architecture of telomere-associated proteins that serve discrete functions is further evidence that shared protein motifs, as exemplified by the signature OB-fold, do not always determine what biochemical task a protein accomplishes but rather signal where it does it.

Or as Lundblad concluded, “What we now propose that this particular protein fold, which both Est3 and TPP1 exhibit, is uniquely suited to the telomere.”

Researchers who also contributed to the study include graduate student Timothy Tucey and Danna Morris, a former graduate student in Lundblad’s lab.

The research was supported by funding from the National Institute on Aging at the NIH.

Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.

Mauricio Minotta | Newswise Science News
Further information:
http://www.salk.edu

Further reports about: DNA Est1 Est3 Lundblad Molecular Protein RNA TPP1 Telomerase Telomere Telomere-building amino amino acids chromosomes telomeric proteins

More articles from Life Sciences:

nachricht New eDNA technology used to quickly assess coral reefs
18.04.2019 | University of Hawaii at Manoa

nachricht New automated biological-sample analysis systems to accelerate disease detection
18.04.2019 | Polytechnique Montréal

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Explosion on Jupiter-sized star 10 times more powerful than ever seen on our sun

A stellar flare 10 times more powerful than anything seen on our sun has burst from an ultracool star almost the same size as Jupiter

  • Coolest and smallest star to produce a superflare found
  • Star is a tenth of the radius of our Sun
  • Researchers led by University of Warwick could only see...

Im Focus: Quantum simulation more stable than expected

A localization phenomenon boosts the accuracy of solving quantum many-body problems with quantum computers which are otherwise challenging for conventional computers. This brings such digital quantum simulation within reach on quantum devices available today.

Quantum computers promise to solve certain computational problems exponentially faster than any classical machine. “A particularly promising application is the...

Im Focus: Largest, fastest array of microscopic 'traffic cops' for optical communications

The technology could revolutionize how information travels through data centers and artificial intelligence networks

Engineers at the University of California, Berkeley have built a new photonic switch that can control the direction of light passing through optical fibers...

Im Focus: A long-distance relationship in femtoseconds

Physicists observe how electron-hole pairs drift apart at ultrafast speed, but still remain strongly bound.

Modern electronics relies on ultrafast charge motion on ever shorter length scales. Physicists from Regensburg and Gothenburg have now succeeded in resolving a...

Im Focus: Researchers 3D print metamaterials with novel optical properties

Engineers create novel optical devices, including a moth eye-inspired omnidirectional microwave antenna

A team of engineers at Tufts University has developed a series of 3D printed metamaterials with unique microwave or optical properties that go beyond what is...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

Fraunhofer FHR at the IEEE Radar Conference 2019 in Boston, USA

09.04.2019 | Event News

 
Latest News

New automated biological-sample analysis systems to accelerate disease detection

18.04.2019 | Life Sciences

Explosion on Jupiter-sized star 10 times more powerful than ever seen on our sun

18.04.2019 | Physics and Astronomy

New eDNA technology used to quickly assess coral reefs

18.04.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>