Studying a protein that gives structure to the nucleus of cells, Johns Hopkins researchers stumbled upon mutations associated with familial partial lipodystrophy (FPLD), a rare disease that disrupts normal patterns of fat distribution throughout the body.
"Our findings open new paths for learning how and why fat cells are disproportionately affected by mutations in the protein lamin A, which is found in the nucleus of most cells of the body," says Katherine Wilson, Ph.D., professor of cell biology at the Johns Hopkins University School of Medicine.
According to the researchers, this is the first report that another protein, SUMO1, can attach to lamin A. Importantly, they found that FPLD-causing mutations in lamin A prevent this attachment. Details of the study were published in the Feb. 1 issue of the journal Molecular Biology of the Cell.
Wilson says lamin A is primarily known for giving shape to the nucleus. "It forms networks of strong 'cables' at the nuclear membrane and works with other proteins to create and maintain the three-dimensional environment in which chromosomes are properly organized, protected and expressed," she says.
When the Wilson group made their discovery, they were studying lamin A binding to another protein, actin. Actin can sometimes form a complex with certain SUMO proteins, small proteins often attached to other proteins to alter their functions, their locations and their interactions with additional proteins.
"Sometimes you go into an experiment looking for one thing but you find another," says Wilson. "We wanted to know if lamin A could bind to actin-SUMO1 complexes. Instead, we found that SUMO1 itself attaches to lamin A."
SUMO1 is usually attached to proteins at sites with certain properties; these sites can be predicted by the surrounding amino acids, the basic building blocks of proteins whose blueprints are found in genes. So the researchers searched lamin A's amino acid sequence for predicted binding sites and found five. Using targeted genetic techniques, they created lamin A variants, each with a mutation at a different predicted SUMO1 attachment site. They then added SUMO1 to the mutants and tested whether it could attach to them or not.
Two mutations significantly decreased SUMO1 attachment. One was at a predicted site; the other was unexpectedly in their comparison "control" variant. "Since the mutation site in our control variant was not a predicted SUMO1 attachment site, we were curious about it," explains Wilson. "Mutations in lamin A cause more than 15 different diseases, so we checked the genetic database to see if any diseases were associated with mutations near the SUMO1 attachment site, and FPLD leapt out like a neon sign."
FPLD is a very rare condition that starts around puberty. Fat on the legs of patients is reduced while it accumulates at other locations, including the neck and face. Patients can also become diabetic.
Twenty-four different mutations in lamin A can cause FPLD. To see if two other FPLD-causing mutations near the SUMO1 attachment site affected SUMO1 attachment, the team created these variants and tested them as before. One of the new variants did show decreased SUMO1 attachment. Based on the location of that mutation and one of the other SUMO1-disrupting mutations, the researchers were able to identify a "patch" on the surface of the lamin A protein that is important for SUMO1 attachment.
Exactly how lamin A and SUMO1 connect to FPLD is still a mystery. "We can only speculate on how lamin A and SUMO1 work together to regulate fat cells," says Wilson. "But these results raise new research questions that will hopefully move FPLD studies forward."Other authors of the report include Dan Simon of the Johns Hopkins University School of Medicine and Tera Domaradzki and Wilma Hofmann of the University at Buffalo, The State University of New York.
On the Web:
Link to article: http://dx.doi.org/10.1091/mbc.E12-07-0527
Wilson Lab: http://www.hopkinsmedicine.org/cellbio/dept/WilsonProfile.html
Related stories:Promising Pursuits: Name That Field (the final story of the article) http://www.hopkinsmedicine.org/news/publications/johns_hopkins_health/spring_2011/promising_pursuits
Catherine Kolf | EurekAlert!
World’s Largest Study on Allergic Rhinitis Reveals new Risk Genes
17.07.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Plant mothers talk to their embryos via the hormone auxin
17.07.2018 | Institute of Science and Technology Austria
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
17.07.2018 | Power and Electrical Engineering
17.07.2018 | Life Sciences
16.07.2018 | Physics and Astronomy