Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Beyond genes: Lipid helps cell wall protein fold into proper shape

18.07.2005


It takes more than the genetically coded sequence for a membrane protein to fold and function. Its lipid environment also plays a role.



A protein that provides a vital passage through a bacterium’s outer cell wall will misfold and malfunction if that wall is built of the ’wrong’ material, scientists at The University of Texas Medical School at Houston report in a finding that has long-term implications for understanding diseases caused by misfolded proteins such as cystic fibrosis, Alzheimer’s disease, and mad cow disease.

The paper in today’s Journal of Biological Chemistry by Professor of Biochemistry and Molecular Biology William Dowhan, Ph.D., and colleagues shows that phospholipids, which make up the permeable barrier of cell membranes, play a direct role in the folding of membrane proteins – proteins that penetrate the membrane or bind to either side of it.


"What we’ve demonstrated again is that it’s not just a membrane protein’s genetically determined sequence that dictates how it folds so that it can function properly. Its lipid environment also plays a role," Dowhan said. "People used to assume that specific lipids made no difference."

In the JBC paper, Dowhan and colleagues looked at how a protein called GabP, which transports an amino acid across the membrane of the bacterium E. coli, is affected by the presence of a phospholipid named phosphatidylethanolamine, or PE for short.

Phospholipids, unlike their fatty acid and cholesterol cousins, include a phosphate group that spurs them to form a bilayer with water-friendly outer layers sandwiching an impermeable water-unfriendly inner layer that defines the outer surface of cells. Transport of nutrients and waste material across the cell membrane is then governed by the specific proteins associated with it.

In a strain of E. coli lacking PE, the GabP protein misfolded, with two areas of the protein inverting from their normal structure. The PE-lacking protein’s amino acid transfer rate plummeted to nearly zero, falling 99 percent compared to the transfer rate in unaltered E. coli with PE.

GabP is the third membrane protein that Dowhan and colleagues have shown to be affected by the presence of PE.

The team is using the E. coli model to discover how all proteins fold in the membrane, not just transport proteins such as GabP but also biosynthetic proteins that manufacture complex compounds such as proteins and fats out of simple compounds.

"The next goal now that we’ve defined the phenomenon is to get into the specifics, find the mechanisms by which these proteins fold. What part of the protein interacts with the lipid, and what part of the lipid with the protein?" said Dowhan, who holds the John S. Dunn Sr. Chair in Biochemistry and Molecular Biology and is on the Graduate School of Biomedical Sciences faculty.

Understanding the molecular basis for membrane protein folding will help researchers address serious diseases caused by misfolded proteins. "In cystic fibrosis, Alzheimer’s disease and mad cow disease, the dysfunctional proteins are associated with membranes," Dowhan said.

Membrane proteins make up 30 percent of known proteins. Dowhan estimates another 40 percent are loosely tied to membranes. "So you are looking at possibly 70 percent of biology occurring at or in a lipid membrane surface," Dowhan said.

Membranes and their surface proteins are accessible targets for pharmaceuticals, and most drugs target either membrane proteins on human cells or the membranes of pathogens.

Co-authors of the JBC paper with senior author Dowhan are first author Wei Zhang, Ph.D., a former graduate student who is now a post-doctoral fellow at Stanford University, and post-doctoral fellow Heidi Campbell, Ph.D., of the UT Medical School Department of Biochemistry, and Molecular Biology, and Steven King, Ph.D, associate professor, Department of Integrative Biosciences at Oregon Health & Science University.

Dowhan recently was granted a MERIT award by the National Institute of General Medical Sciences of the National Institutes of Health.

These rare awards provide long-term grant support for scientists whose research competence and productivity are distinctly superior and who are likely to continue to perform in an outstanding manner, the NIGMS notes.

MERIT (Method to Extend Research in Time) status essentially gives Dowhan a 10-year renewal to 2015 on his longstanding NIGMS grant "Structure and Function of Membrane Proteins" by providing back-to-back five-year grants of $2.4 million apiece.

In April, Dowhan received the prestigious American Society for Biochemistry and Molecular Biology Avanti Award in Lipids.

Scott Merville | EurekAlert!
Further information:
http://www.uth.tmc.edu

More articles from Life Sciences:

nachricht Study suggests oysters offer hot spot for reducing nutrient pollution
17.10.2017 | Virginia Institute of Marine Science

nachricht World first for reading digitally encoded synthetic molecules
17.10.2017 | CNRS

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

Im Focus: New nanomaterial can extract hydrogen fuel from seawater

Hybrid material converts more sunlight and can weather seawater's harsh conditions

It's possible to produce hydrogen to power fuel cells by extracting the gas from seawater, but the electricity required to do it makes the process costly. UCF...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Study suggests oysters offer hot spot for reducing nutrient pollution

17.10.2017 | Life Sciences

Breaking: the first light from two neutron stars merging

17.10.2017 | Physics and Astronomy

World first for reading digitally encoded synthetic molecules

17.10.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>