ScienceDaily (May 31, 2012) The 20 proteins in the Wnt family are some of the most important proteins in controlling how an organism develops and grows, but for 30 years scientists have not known what these vital proteins actually look like. The proteins have eluded standard visualization techniques, in large part because they do not dissolve well in the water-based liquids normally used for biochemical studies. But once Howard Hughes Medical Institute investigator K. Christopher Garcia, and Claudia Janda, a post-doctoral fellow in his Stanford University School of Medicine lab, thought of an approach to make the proteins behave better, they succeeded in solving the first structure of a Wnt protein.
Their work, published online May 31, 2012, in Science Express, reveals an unexpected three-dimensional shape that offers clues to how Wnt proteins function and clarifies the nature of its Frizzled receptor target for drug developers working to design anti-Wnt therapies for cancer and other diseases. "Having finally gained structural access to Wnts, I think this is going to open up a whole new era in molecularly dissecting the role of Wnt proteins in biological processes," says Garcia.
Wnt proteins were discovered 30 years ago by Harold Varmus, the current director of the National Cancer Institute, and Roel Nusse, who is now an HHMI investigator at Stanford University. They observed that Wnt1, the gene for a Wnt protein, was very active in breast cancer cells from mice. Over the past decades, researchers have shown that Wnt proteins play key roles in embryonic development, tissue regeneration, bone growth, stem cell differentiation, as well as many human cancers. In essence, Wnt proteins help give cells their identity and tell them how to behave.
"This is one of the most important ligand-receptor systems in both human and invertebrate biology. Wnts cut across every field, which is why I got involved. But many excellent groups have tried to express them in the lab and solve their structures, so we realized that something non-intuitive would be required to crack the problem," says Garcia.
In 2003, Nusse's team found out why scientists who had been trying to isolate Wnt proteins had been plagued with so many difficulties: the proteins contained lipids, fatty molecules that prevent the protein from dissolving in water-based solutions. Scientists realized they could stabilize the protein by instead keeping it in mixtures that contained detergents, helping pave the way for a plethora of biochemical experiments on isolated Wnts. But such detergent-containing mixtures still present obstacles for crystallizing and visualizing proteins by structural analysis techniques; simply put, the detergents get in the way.
"This really causes a great deal of difficulty in working with these proteins," says Garcia. But he and Janda had an idea: what if they expressed both a Wnt protein, and the receptor it bound to in the same cell? Perhaps, they thought, the receptor would shield the Wnt protein's exposed lipid, making it able to dissolve in the solution they needed.
The technique worked -- they were able to produce Wnt8 bound to Frizzled-8, one of 10 Frizzled receptors that the 20 Wnt proteins bind to to carry out cellular effects.
"It's one of the most unusual protein structures I've ever seen," says Garcia. "It looks like a crab with its two pinchers reaching around and grabbing the Frizzled receptor. When we originally solved this, we could see no relationship between the structure of Wnt8 and any other structure that has ever been described. However, we are beginning to see the evolutionary origins of the Wnt fold. This story is developing."
Garcia expects the other Wnt proteins likely have similar structures, with the respective Frizzled receptors shielding the lipid attached to the protein, meaning their method should work on other Wnts. He now wants to delve into those structures, answering questions about which Wnt-Frizzled pairs are responsible for what biological roles, how co-receptors bind to the pairs, and how the structure can be changed to optimize the interactions.
"What we can see now are some clues in the structure as to why Wnts are so hard to express, because of the exposure of the lipid," says Garcia. "So now we can think about ways to remodel the protein that will solve the expression problem without altering function."
View original post here:
New molecular structure offers first picture of a protein family vital to human health
- Podcast 9 Athens part 3 and news - November 8th, 2009 [November 8th, 2009]
- Podcast 10 Athens part 4 - November 8th, 2009 [November 8th, 2009]
- Podcast 11 Athens Part 5 - November 8th, 2009 [November 8th, 2009]
- Episode 12 Cardiac Nuclear Medicine in the UK - November 8th, 2009 [November 8th, 2009]
- Podcast 13 Choline PET and prostate cancer - November 8th, 2009 [November 8th, 2009]
- Episode14 ED function and Dysponea - November 8th, 2009 [November 8th, 2009]
- ep 15 Collimator Choice and Reconstruction algorithm - November 8th, 2009 [November 8th, 2009]
- Episode 16 Dr Strauss on vulnerable plaque - November 8th, 2009 [November 8th, 2009]
- Episode17 Chemical Stress - November 8th, 2009 [November 8th, 2009]
- Episode 18 Myocardial Perfusion Imaging and Diabetes - November 8th, 2009 [November 8th, 2009]
- Episode 19 The INSPIRE trial - November 8th, 2009 [November 8th, 2009]
- 20 Dual isotope with a difference - November 8th, 2009 [November 8th, 2009]
- Episode 21 The real effect of stress - November 8th, 2009 [November 8th, 2009]
- Episode 22 D-SPECT - November 8th, 2009 [November 8th, 2009]
- Episode 23 VQ Reprise - November 8th, 2009 [November 8th, 2009]
- Episode 24 Hepatobiliary Nuclear Medicine - November 8th, 2009 [November 8th, 2009]
- Episode 25 Sleep Apnea - November 8th, 2009 [November 8th, 2009]
- Episode 26 Imaging Post Traumatic Stress Disorder - November 8th, 2009 [November 8th, 2009]
- Episode 27 Cardiac Stem Cells - November 8th, 2009 [November 8th, 2009]
- Episode 28 Molly Supply - November 8th, 2009 [November 8th, 2009]
- Episode 29 Melanoma therapy interview with Dr Ekaterina Dadachova - November 8th, 2009 [November 8th, 2009]
- Episode 30 Viral Therapy - November 8th, 2009 [November 8th, 2009]
- Episode 31 breast radiotherapy using radioisotopes - November 8th, 2009 [November 8th, 2009]
- Episode 32 news from snm - November 8th, 2009 [November 8th, 2009]
- Episode 33 EBV Imaging and Therapy - November 8th, 2009 [November 8th, 2009]
- Episode 34 Dr Lele SNM India 2009 - December 14th, 2009 [December 14th, 2009]
- Episode 35 Dr Andrew Scott from the Ludwig institute - January 10th, 2010 [January 10th, 2010]
- Episode 36 CardiArc - February 25th, 2010 [February 25th, 2010]
- Episode 37 Dr Modder Radiosynoviorthesis (Radiation Synovectomy) - March 31st, 2010 [March 31st, 2010]
- Episode 38 Indian Nuclear Medicine With Dr Malhotra and Dr Krishna - May 28th, 2010 [May 28th, 2010]
- Episode 39 Prof Ora Israel The Utility of Hybrid Imaging - July 13th, 2010 [July 13th, 2010]
- Episode 40 New V/Q SPECT developments - October 11th, 2010 [October 11th, 2010]
- Episode 41 scintimun - February 14th, 2011 [February 14th, 2011]
- Episode 42 Radio-Isotope Supply into the future - March 6th, 2011 [March 6th, 2011]
- Podcast 4: DNA therapy - April 24th, 2011 [April 24th, 2011]
- Sorry about the delay a new podcast will be out soon! - April 24th, 2011 [April 24th, 2011]
- Podcast 5 Flash 3D - April 24th, 2011 [April 24th, 2011]
- Podcast 6 Affibody - April 24th, 2011 [April 24th, 2011]
- Podcast 7 EANM 2006 Athens Part 1 - April 24th, 2011 [April 24th, 2011]
- Podcast 8 Athens Part 2 - April 24th, 2011 [April 24th, 2011]
- Episode 43 Rapidscan Part 1, 720P high quality video version - May 1st, 2011 [May 1st, 2011]
- Episode 43 Rapidscan Part 1, Ipod quality video - May 1st, 2011 [May 1st, 2011]
- Episode 43 Rapidscan Part 1, Audio version - May 1st, 2011 [May 1st, 2011]
- Episode 45 Mummies with cardiovascular disease video - May 21st, 2011 [May 21st, 2011]
- Episode 45 Mummies with cardiovascular disease audio edition - May 21st, 2011 [May 21st, 2011]
- Episode 46 Dr Gordon DePuey Choosing Reconstruction clinical perspective - August 7th, 2011 [August 7th, 2011]
- Episode 46 Dr Gordon DePuey Choosing Reconstruction clinical perspective audio version - August 7th, 2011 [August 7th, 2011]
- Episode 47 Cardiac Image Fusion With Dr Kaufmann - September 18th, 2011 [September 18th, 2011]
- Episode 47 Cardiac Fusion with Dr Kaufmann video version - September 18th, 2011 [September 18th, 2011]
- Dear Steve, I am and many more like me are your one more thing. - October 9th, 2011 [October 9th, 2011]
- EPISODE 48 PET MRI camera from Siemens with Dr Georgi audio - October 23rd, 2011 [October 23rd, 2011]
- EPISODE 48 PET MRI camera from Siemens Dr Georgi video - October 23rd, 2011 [October 23rd, 2011]
- Silicon Biosystems to Present Single-Circulating Tumor Cell Molecular Characterization at the Fourth World CTC Summit - April 25th, 2012 [April 25th, 2012]
- Leukaemia cells have a remembrance of things past - April 25th, 2012 [April 25th, 2012]
- Technologist Education Requirements Can Help Cut Repeat Scans - April 25th, 2012 [April 25th, 2012]
- HKU Collaborative Research Discovers A Novel Molecular Mechanism Of A New Anti-HIV-1 Drug Candidate - April 25th, 2012 [April 25th, 2012]
- Focal Segmental Glomerulosclerosis and the Nephrotic Syndrome - Part 1 Clinical - Video - May 4th, 2012 [May 4th, 2012]
- Electro-Medicine : Biological Physics - The Molecular Basis of Alzheimers Disease - Video - May 4th, 2012 [May 4th, 2012]
- osdd heterocyclic compounds and molecular medicines - Video - May 4th, 2012 [May 4th, 2012]
- Molecule to Medicine: The Biomarker Frontier - Video - May 4th, 2012 [May 4th, 2012]
- Fulfilling the Promise of Molecular Medicine in a Developmental Brain Disorder - Video - May 4th, 2012 [May 4th, 2012]
- Focus on Stefanie Dimmeler - Video - May 4th, 2012 [May 4th, 2012]
- Dundee - May 4th, 2012 [May 4th, 2012]
- Nanotechnology In Medicine: Huge Potential, But What Are The Risks? - May 5th, 2012 [May 5th, 2012]
- Cutting Edge Technology Coming To DMH - May 5th, 2012 [May 5th, 2012]
- This Week in Experimental and Molecular Pathology - May 5th, 2012 [May 5th, 2012]
- Researchers' discovery offers hope for cancer, heart disease miracle drugs - May 7th, 2012 [May 7th, 2012]
- Penn State student Zachary Hostetler from Garnet Valley is being honored as a student marshal - May 7th, 2012 [May 7th, 2012]
- NCKU Student Wins Prestigious Award for Anti-Cancer Research - May 10th, 2012 [May 10th, 2012]
- In-Vitro Diagnostics (IVD) Market (Clinical Chemistry, Immunoassays, Molecular Diagnostics, Hematology Analyzers ... - May 10th, 2012 [May 10th, 2012]
- Pitt team uses genomics to identify a molecular-based treatment for a viral skin cancer - May 10th, 2012 [May 10th, 2012]
- Genomics used to identify a molecular-based treatment for a viral skin cancer - May 10th, 2012 [May 10th, 2012]
- 2 molecular biologists get $500K medical prize - May 13th, 2012 [May 13th, 2012]
- 2 molecular biologists share $500K medical prize - May 13th, 2012 [May 13th, 2012]
- Lab21 Unveils New Molecular Analysis Services at Greenville Site - May 13th, 2012 [May 13th, 2012]
- 2 molecular biologists from NYC to share $500K medical prize for pioneering research on cells - May 13th, 2012 [May 13th, 2012]
- Two Molecular Biologists Get $500K Medical Prize - May 13th, 2012 [May 13th, 2012]
- Pair of molecular biologists receive Albany Medical Center Prize - May 13th, 2012 [May 13th, 2012]
- CNIO scientists successfully test the first gene therapy against aging-associated decline - May 16th, 2012 [May 16th, 2012]
- Cancer Institute of New Jersey Aims to Advance Personalized Cancer Treatments Through 'Precision Medicine' - May 16th, 2012 [May 16th, 2012]