Natalie Ahn

Kinase activation by small conformational changes

Anonymous — Fri, 22 Nov 2019 18:38:05 +0000

Kinase activation by small conformational changes Anonymous (not verified) Fri, 11/22/2019 - 11:38

Protein Kinases (PKs) are allosteric enzymes that play an essential role in signal transduction by regulating a variety of key cellular processes. Most PKs suffer con- formational rearrangements upon phosphorylation that strongly enhance the catalytic activity. Generally, it involves the movement of the phosphorylated loop towards the active site and the rotation of the whole C-terminal lobe. However, not all kinases un- dergo such a large configurational change: The MAPK extracellular signal-regulated protein kinases ERK1 and ERK2 achieve a 50,000 fold increase in kinase activity with only a small motion of the C-terminal region. In the present work, we used a combi- nation of molecular simulation tools to characterize the conformational landscape of ERK2 in the active (phosphorylated) and inactive (unphosphorylated) states in solu- tion in agreement with NMR experiments. We show that the chemical reaction barrier is strongly dependent on ATP conformation and that the ‘active’ -low barrier- con- figuration is subtly regulated by phosphorylation, which stabilizes a key salt bridge between the conserved Lys52 and Glu69 belonging to helix-C and promotes binding of a second Mg ion. Our study highlights that the on-off switch embedded in the kinase fold can be regulated by small, medium and large conformational changes.

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Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2

Anonymous — Thu, 31 Oct 2019 17:32:44 +0000

Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2 Anonymous (not verified) Thu, 10/31/2019 - 11:32

Conformational selection by small molecules expands inhibitory possibilities for protein kinases. Nuclear magnetic resonance (NMR) measurements of the mitogen-activated protein (MAP) kinase ERK2 have shown that activation by dual phosphorylation induces global motions involving exchange between two states, L and R. We show that ERK inhibitors Vertex-11e and SCH772984 exploit the small energetic difference between L and R to shift the equilibrium in opposing directions. An X-ray structure of active 2P-ERK2 complexed with AMP-PNP reveals a shift in the Gly-rich loop along with domain closure to position the nucleotide in a more catalytically productive conformation relative to inactive 0P-ERK2:ATP. X-ray structures of 2P-ERK2 complexed with Vertex-11e or GDC-0994 recapitulate this closure, which is blocked in a complex with a SCH772984 analog. Thus, the L→R shift in 2P-ERK2 is associated with movements needed to form a competent active site. Solution measurements by hydrogen-exchange mass spectrometry (HX-MS) reveal distinct binding interactions for Vertex-11e, GDC-0994, and AMP-PNP with active vs. inactive ERK2, where the extent of HX protection correlates with R state formation. Furthermore, Vertex-11e and SCH772984 show opposite effects on HX near the activation loop. Consequently, these inhibitors differentially affect MAP kinase phosphatase activity toward 2P-ERK2. We conclude that global motions in ERK2 reflect conformational changes at the active site that promote productive nucleotide binding and couple with changes at the activation loop to allow control of dephosphorylation by conformationally selective inhibitors.

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Recommendations for performing, interpreting and reporting hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments

Anonymous — Thu, 17 Oct 2019 18:10:10 +0000

Recommendations for performing, interpreting and reporting hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments Anonymous (not verified) Thu, 10/17/2019 - 12:10

Hydrogen deuterium exchange mass spectrometry (HDX-MS) is a powerful biophysical technique being increasingly applied to a wide variety of problems. As the HDX-MS community continues to grow, adoption of best practices in data collection, analysis, presentation and interpretation will greatly enhance the accessibility of this technique to nonspecialists. Here we provide recommendations arising from community discussions emerging out of the first International Conference on Hydrogen-Exchange Mass Spectrometry (IC-HDX; 2017). It is meant to represent both a consensus viewpoint and an opportunity to stimulate further additions and refinements as the field advances.

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Biochemists untangle mysteries of cellular form, function

Anonymous — Thu, 25 Apr 2019 06:00:00 +0000

Biochemists untangle mysteries of cellular form, function Anonymous (not verified) Thu, 04/25/2019 - 00:00

Trent Knoss

The complex inner workings of cells, from their architecture to their signaling, underlie much of multicellular organic life. How are they built? How do their proteins interact? And most crucially, how can understanding these functions improve our knowledge of biological outcomes such as disease?

�鶹ӰԺ Distinguished Professors Karolin Luger and Natalie Ahn have studied questions such as these for decades. Last year, both were elected to the National Academy of Sciences, one of the most prestigious honors a scientist can receive. The duo will be formally inducted on Saturday, April 27 at the organization’s annual meeting.

“It’s a high honor because it comes from peers,” said Luger, the endowed chair of CU �鶹ӰԺ’s Department of Biochemistry and a Howard Hughes Medical Institute Investigator. “It’s primarily a wonderful acknowledgement of the collective work of all the former and present students, post-docs and technicians who have contributed to this research.”

Like an archeologist piecing together the origins of ancient structures, Luger and her students examine the fundamental building blocks of genomic processes and untangle their cellular machinery.

Luger began her career with an interest in x-ray crystallography, a technique used to discern 3D molecular structures. Eventually, her focus shifted to chromatin, the material that holds DNA, RNA and proteins together in a compact package within eukaryotic cells. As recently as the late 1980s, before the advent of the Human Genome Project, chromatin was thought to be unimportant, similar to packaging material that only serves to hold more valuable items inside.

“It was a binary mentality back then, but it turned out to be much messier, with lots of variation between individual cells,” Luger said. “The packaging, so to speak, has very important implications for how cell types differentiate.”

Imagine a space filled with labeled cardboard boxes full of books, she says. By reading the labels on the boxes, humans can discern which boxes they’ll need soon and which ones they can safely stash away. Chromatin operates similarly: A fertilized egg cell needs everything—all the genomic information it can get—whereas a more mature cell, such as a liver cell, can read the packaging and know what it can safely ignore.

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Natalie Ahn and Roy Parker named CU Distinguished Professors

Anonymous — Fri, 14 Sep 2018 06:00:00 +0000

Natalie Ahn and Roy Parker named CU Distinguished Professors Anonymous (not verified) Fri, 09/14/2018 - 00:00

With approval Sept. 14 by the Board of Regents, the University of Colorado has introduced seven newly designated distinguished professors, six of whom are affiliated with the CU �鶹ӰԺ campus.

They are Natalie Ahn, James Anaya, Elizabeth Fenn, John Lynch, Warren Motte and Roy Parker. From the CU Anschutz Medical Campus, Larry Green also was designated a distinguished professor.

Distinguished professors are faculty members who demonstrate exemplary performance in research or creative work, a record of excellence in classroom teaching and supervision of individual learning, and outstanding service to the profession, the university and its affiliates.

The CU campuses nominate faculty for the award, the highest honor bestowed upon faculty across the system's four campuses. President Benson then reviews the nominations and, with the recommendation of the Distinguished Professors Committee, forwards the candadates' names to the Board of Regents.

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National Academy of Sciences inducts 2 CU �鶹ӰԺ professors

Anonymous — Mon, 07 May 2018 06:00:00 +0000

National Academy of Sciences inducts 2 CU �鶹ӰԺ professors Anonymous (not verified) Mon, 05/07/2018 - 00:00

Colorado Arts and Sciences Magazine

Pioneering biochemists Natalie Ahn and Karolin Luger have been inducted into the National Academy of Sciences, an honor that recognizes "distinguished and continuing achievements in original research." Membership in the prestigious organization is widely considered to be one of the highest honors that a scientist can receive.

"It's really a wonderful recognition of our work and a great honor that I share with all of my coworkers, past and present," said Luger, a professor in the Department of Chemistry and Biochemistry and the Jennie Smoly Caruthers Endowed Chair of Biochemistry.

Luger and her colleagues study how genetic material is stored in human cells and how these organizational principles critically affect every aspect of cell life in health and disease. Understanding and visualizing protein-DNA assemblies at atomic resolution will allow researchers to better understand how the genome is decoded by the cell’s machinery.

In 2017, Luger—who is also a Howard Hughes Medical Institute (HHMI) Investigator—published research on the genomic structure of microbes called Archaea, findings that hinted at the evolutionary origins of DNA folding that all multicellular organisms use. The research built on Luger's cornerstone scientific achievement, which outlined the three-dimensional structure of the nucleosome. That finding, now widely cited in textbooks, was named the “breakthrough of the year” in 1997 by the journal Science.

Ahn joined the CU �鶹ӰԺ faculty in 1992 and served as an HHMI Investigator from 1994–2014. She serves as President of the American Society of Biochemistry and Molecular Biology.

“This is such a great honor," said Ahn, a Professor of Distinction in Chemistry and Biochemistry and Associate Director of the BioFrontiers Institute. "I owe many thanks to my past mentors, and to my wonderful colleagues, students and friends in our amazing CU �鶹ӰԺ community.”

Ahn's research focuses on enzymatic and cellular mechanisms underlying cell signal transduction. She conducted pioneering work in the discovery of the mitogen-activated protein (MAP) kinase cascade, including the identification of MAP kinase kinases which are important targets for anti-cancer therapies. She was also a pioneer in the use of functional proteomics and mass spectrometry for signal transduction research.

The 2018 class of National Academy of Sciences inductees includes 84 researchers from across the country as well as 21 foreign associates. The new inductees bring the total number of active members to 2,382 and the total number of foreign associates to 484.

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Professors honored for work in cell signals, ultrafast lasers

Anonymous — Fri, 20 Apr 2018 06:00:00 +0000

Professors honored for work in cell signals, ultrafast lasers Anonymous (not verified) Fri, 04/20/2018 - 00:00

Two CU �鶹ӰԺ professors are among the latest group of scientists, politicians, artists and more elected to the American Academy of Arts and Science. The academy, which was founded in 1780 and has claimed such luminaries as Albert Einstein and Margaret Mead as members, “honors exceptional scholars, leaders, artists, and innovators and engages them in sharing knowledge and addressing challenges facing the world.”

Among this elite organization’s newly elected members are Natalie Ahn, a CU �鶹ӰԺ biochemist who explores cell signaling, and Henry Kapteyn, a CU �鶹ӰԺ physicist who has led the development of new types of lasers. The academy announced its 2018 class earlier this week, which includes former President Barack Obama, actor Tom Hanks, writer Ta-Nehisi Coates and more than 200 other leading thinkers.

Ahn and Kapteyn will be officially inducted into the academy’s membership at a ceremony in October 2018.

Cell signals

Natalie Ahn joined CU �鶹ӰԺ’s Department of Chemistry and Biochemistry in 1992. She uses a technique called mass spectrometry to probe how cells communicate with each other and their environments—and how these processes can regulate the way that cells grow and divide and, potentially, give rise to cancers like melanoma.

Ahn is director of CU �鶹ӰԺ’s Graduate Training Program in Signaling and Cellular Regulation, associate director of the BioFrontiers Institute and president of the American Society of Biochemistry and Molecular Biology (ASBMB).

Reflecting on her appointment, Ahn said: “I am deeply grateful for the tremendous honor of being elected to the American Academy of Arts and Sciences. I am flabbergasted, humbled and very happy. I have a lot of people to thank in my life, as well as at our amazing university, for their support throughout my career and for their work to further the arts and sciences in the United States. I will work hard to pay it forward.”

Harnessing lasers

Henry Kapteyn, a professor in the Department of Physics and fellow at JILA, has been at CU �鶹ӰԺ since 1999. He and his wife, CU �鶹ӰԺ Professor Margaret Murnane, have spearheaded new “tabletop” X-ray lasers, devices that can shoot out laser light in bursts shorter than a millionth of a billionth of a second. The team’s work has led to insights on the workings of atoms and the creation of new nanotechnologies.

Kapteyn is a fellow at the American Physical Society (APS) and the American Association for the Advancement of Science (AAAS) and, along with Murnane, founded the company KMLabs.

"The Department of Physics is proud to have Professor Henry Kapteyn honored with membership in the American Academy of Arts and Sciences,” said John Cumalat, Chair of the Department of Physics. “Professor Kapteyn has won several awards for his research in ultrafast laser science. In 2013 he was elected to the National Academy of Sciences. This award is continued recognition of his pioneering impact on the field."

“I’m stunned and tremendously honored to be welcomed to a group as illustrious as the American Academy of Arts and Sciences,” Kapteyn said. “I certainly never imagined being found on the same list with Barack Obama. But it’s a tremendous motivation to keep pushing forward—to turn my passion for using physics to make the impossible, possible—into a real benefit to society.”

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